CN1260795A - quaternary ammonium compounds as tachykinin antagonists - Google Patents

quaternary ammonium compounds as tachykinin antagonists Download PDF

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CN1260795A
CN1260795A CN98806342A CN98806342A CN1260795A CN 1260795 A CN1260795 A CN 1260795A CN 98806342 A CN98806342 A CN 98806342A CN 98806342 A CN98806342 A CN 98806342A CN 1260795 A CN1260795 A CN 1260795A
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phenyl
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dichlorophenyl
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CN1199971C (en
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S·M·莫纳格汉
D·阿尔克
C·J·伯恩斯
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Pfizer Inc
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Abstract

The invention provides a compound of formula wherein R is phenyl, C3－C7Cycloalkyl or heteroaryl, said radicals optionally being benzo-or C3－C7Cycloalkyl is fused and optionally substituted with 1-3 substituents, including in benzo-or C3－C7Substituted in the fused part of the cycloalkyl radicals, the substituents being independently of one another selected from C1－C4Alkyl, fluoro (C)1－C4) Alkyl radical, C1－C4Alkoxy, fluoro (C)1－C4) Alkoxy, phenoxy, C2－C4Alkanoyl, halogen, C1－C4Alkoxycarbonyl group, C3－C7Cycloalkyl, -S m(C1－C4) Alkyl, cyano, -NR2R3、－S(O)mNR2R3、－NR4(C1－C4Alkanoyl) and-CONR2R3Or R is 2, 3-dihydrobenzo [ b ]]Furyl or chromanyl radical, R1Is H or C1－C6Alkyl, W is a direct bond, methylene or ethylene, X is a straight chain C2－C4Y is phenyl, naphthyl, benzyl, pyridyl, thienyl or C3－C7Cycloalkyl which is optionally substituted by 1 to 3 substituents selected independently of one another from C1－C4Alkyl, fluoro (C)1－C4) Alkyl radical, C1－C4Alkoxy, fluoro (C)1－C4) Alkoxy, halogen and cyano, Ar is phenyl, naphthyl, benzyl, thienyl, benzo [ b ]]Thienyl or indolyl, each of which is optionally substituted with 1 to 3 substituents independently selected from C1－C4Alkyl, fluoro (C)1－C4) Alkyl radical, C1－C4Alkoxy, fluoro (C)1－C4) Alkoxy, halogen and cyano, or Ar is 1, 3-benzodioxolan-4-or-5-yl or 1, 4-benzodioxan-5-or-6-yl, ZAIs a pharmaceutically acceptable anion, with the proviso that when W is a direct bond and R is an optionally fused and optionally substituted heteroaryl group, said heteroaryl group is attached to the carbonyl group through a ring carbon atom. The compounds are tachykinin antagonists.

Description

Quaternary ammonium compound as tachykinin antagenists
The present invention relates to quaternary ammonium compound.More particularly, the present invention relates to 1-(2-acylimidazole-1-base alkyl) rubane (quinuclidinium) salt compound and preparation method thereof, be used to prepare the intermediate of this class salt, contain the purposes of composition and this class salt of this class salt.
Compound of the present invention is a tachykinin antagenists, and described tachykinin comprises NKA (neurokinin A), NKB (neurokinin B) and P material, and they act on neurokinine-1 (NK in human body 1), neurokinin-2 (NK 3) and neurokinin-3 (NK 3) acceptor.
These compounds especially can be used as NK 1And NK 2The dual antagonist of acceptor, therefore can be used for treating diseases associated with inflammation, sacroiliitis for example, psoriasis, asthma or inflammatory bowel, central nervous system (CNS) disease, as anxiety, depressed, dementia or psychosis, stomach and intestine (GI) disease, as the function enteropathy, irritable bowel syndrome, gastroesophageal reflux, scoracratia, colitis or regional ileitis, the disease that causes by the gram negative bacterium of helicobacter pylori or another kind of urease-positive, the urogenital tract disease, for example incontinence, impotence, hyperreflexia or urocystitis, tuberculosis, for example chronic disordered breathing tract disease, allergy, eczema for example, contact dermatitis, atopic dermatitis, urticaria, eczematoid dermatitis or rhinitis, anaphylactic disease, toxicodendron allergy for example, proliferative disease, cancer or relate to the disease of fibroblast proliferation for example, vasospasm disease, vasculogenesis for example, angina or Reynaud disease, fibrous tissue forms or collagen disease, atherosclerosis for example, scleroderma or acidophilia fascioliasis hepatica, reflection (reflux) sympathetic nerve malnutrition, shoulder/hand syndromes for example, addictive disorders, alcoholism for example, the body illness relevant with anxiety, peripheral neurophaty, diabetic neuropathy for example, neurodynia, cusalgia, the painful neuropathy, (burn) burns, herpetic neurodynia or postherpetic neuralgia, the neuropathology disease, for example Alzheimer's disease or multiple sclerosis, with immunostimulant or inhibition diseases associated, systemic lupus erythematous for example, rheumatosis, fibrositis for example, vomiting, cough, acute and chronic pain, migraine, ophthalmic diseases, for example proliferating retinopathy, influenza or cold.
EP-A-680962 and EP-A-0739891 disclose and have been the heterogeneous ring compound of non-peptide class NKA antagonist, and they are used for the treatment of for example disease such as asthma.EP-A-0591040 discloses has the active quaternary ammonium compound of tachykinin antagenists.
The invention provides formula (I) compound: Wherein R is a phenyl, C 3-C 7Cycloalkyl or heteroaryl, described group can at random be benzo-or C 3-C 7Cycloalkylfused, and can at random be replaced by 1～3 substituting group, be included in benzo-or C 3-C 7Be substituted in the Cycloalkylfused part, described substituting group is independently from each other C 1-C 4Alkyl, fluoro (C 1-C 4) alkyl, C 1-C 4Alkoxyl group, fluoro (C 1-C 4) alkoxyl group, phenoxy group, C 2-C 4Alkanoyl, halogen, C 1-C 4Alkoxy carbonyl, C 3-C 7Cycloalkyl ,-S (O) m(C 1-C 4) alkyl, cyano group ,-NR 2R 3,-S (O) mNR 2R 3,-NR 4(C 1-C 4Alkanoyl) and-CONR 2R 3, perhaps R is 2,3-dihydrobenzo [b] furyl or chromanyl; R 1Be H or C 1-C 6Alkyl; R 2And R 3Be independently from each other H and C 1-C 6Alkyl, perhaps the two represents C together 4-C 6Alkylidene group; R 4Be H or C 1-C 6Alkyl; W is direct key, methylene radical or ethylidene; X is a straight chain C 2-C 4Alkylidene group; Y is phenyl, naphthyl, benzyl, pyridyl, thienyl or C 3-C 7Cycloalkyl, they can at random be independently from each other following substituting group by 1～3 separately and replace: C 1-C 4Alkyl, fluoro (C 1-C 4) alkyl, C 1-C 4Alkoxyl group, fluoro (C 1-C 4) alkoxyl group, halogen and cyano group; Ar is phenyl, naphthyl, benzyl, thienyl, benzo [b] thienyl or indyl, and they can at random be independently from each other following substituting group by 1-3 separately and replace: C 1-C 4Alkyl, fluoro (C 1-C 4) alkyl, C 1-C 4Alkoxyl group, fluoro (C 1-C 4) alkoxyl group, halogen and cyano group, perhaps Ar is 1,3-benzo dioxolane-4-or-5-base or 1,4-benzodioxan-5-or-the 6-base; M is 0,1 or 2; Z AIt is pharmaceutically acceptable negatively charged ion; " heteroaryl " that uses in the R definition is meant thienyl or contains 1～4 nitrogen heteroatom or 5 or 6 yuan of ring heteroaryls of 1 or 2 nitrogen heteroatom and 1 oxygen or sulfur heteroatom, condition be when W be direct key and R when being any condensed and any substituted heteroaryl, described heteroaryl links to each other with carbonyl by ring carbon atom.
In above-mentioned definition; " halogen " is meant fluorine, chlorine, bromine or iodine, has the alkyl and the alkoxyl group of three or three above carbon atoms, the alkylidene group (except as otherwise noted) that has the alkanoyl of four carbon atom and have two or more carbon atoms can be side chain or straight chain.
Z ABe pharmaceutically acceptable negatively charged ion, for example chlorion, bromide anion, nitrate radical, methanesulfonate, tosic acid root, Phenylsulfonic acid root, bisulfate ion or sulfate radical.
Z APreferably chlorion or methanesulfonate.
Z AIt most preferably is methanesulfonate.
Formula (I) compound contains one or more unsymmetrical carbons, therefore has two or more stereoisomeric forms in any ratio.The present invention includes the single steric isomer of formula (I) compound and their mixture.
The separation of diastereomer can adopt routine techniques to carry out, for example by fractional crystallization, chromatography or HPLC formula (I) compound or its suitable salt or the three-dimensional heterogeneous mixture of derivative.The single enantiomorph of formula (I) compound also can or for example pass through HPLC by corresponding optical purity intermediate preparation, split corresponding racemic modification preparation with suitable chiral support, perhaps the diastereo-isomerism salt preparation that forms by corresponding racemic modification and the optically active acid-respons that suits by fractional crystallization.
R is phenyl preferably, and it can at random be benzo-or C 3-C 7Cycloalkylfused, and can at random be replaced by 1,2 or 3 substituting group, be included in benzo-or C 3-C 7Replace in the Cycloalkylfused part, described substituting group is independently from each other C 1-C 4Alkyl, fluoro (C 1-C 4) alkyl, C 1-C 4Alkoxyl group, fluoro (C 1-C 4) alkoxyl group, phenoxy group and halogen or R be 2,3-dihydrobenzo [b] furyl.
R is more preferably phenyl, and it can at random be benzo-or C 3-C 7Cycloalkylfused, and can at random be replaced by 1,2 or 3 substituting group, be included in benzo-or C 3-C 7Replace in the Cycloalkylfused part, described substituting group is independently from each other methyl, ethyl, trifluoromethyl, methoxyl group, isopropoxy, trifluoromethoxy, phenoxy group, fluorine and chlorine, and perhaps R is 2,3-dihydrobenzo [b] furyl.
R also is more preferably phenyl, naphthyl or tetralyl, they can at random be independently selected from following substituting group by 1,2 or 3 separately and replace: methyl, ethyl, trifluoromethyl, methoxyl group, isopropoxy, trifluoromethoxy, phenoxy group, fluorine and chlorine, perhaps R is 2,3-dihydrobenzo [b] furyl.
R is phenyl preferably further, 3,5-3,5-dimethylphenyl, 2,3-3,5-dimethylphenyl, 2-Trifluoromethoxyphen-l, 2-methoxyl group-3-aminomethyl phenyl, 2,3-dihydrobenzo [b] furans-7-base, naphthalene-2-base, 4-fluoro-3-trifluoromethyl, 1,2,3,4-naphthane-5-base, 1,2,3,4-naphthane-6-base, 5-chloro-2-p-methoxy-phenyl, 2-p-methoxy-phenyl, 2-trifluoromethyl, 2-isopropyl phenyl, 2-ethylphenyl, 2-Phenoxyphenyl or 3,5-two (trifluoromethyl) phenyl.
R most preferably is 2,3-3,5-dimethylphenyl, naphthalene-2-base, 1,2,3,4-naphthane-5-base or 2-p-methoxy-phenyl.
R 1H preferably.
W is a direct key or a methylene radical preferably.
W most preferably is a direct key.
X is ethylene preferably.
Y is phenyl, naphthyl or cyclohexyl preferably, and they separately can be at random by 1,2 or 3 C 1-C 4Alkyl substituent replaces.
Y is more preferably phenyl, and 3,5-3,5-dimethylphenyl, cyclohexyl or naphthalene-2-base.
Y most preferably is a phenyl.
The phenyl that Ar preferably can at random be replaced by 1,2 or 3 halogenic substituent.
Ar is more preferably the phenyl that is replaced by 1 or 2 chlorine.
Ar most preferably is 3, the 4-dichlorophenyl.
The preferred embodiment of formula (I) compound is the compound of formula (IA):
Figure A9880634200141
Wherein 1) R-W-is 3, and 5-3,5-dimethylphenyl, Y are phenyl and Z ABe CH 3SO 3 -2) R-W-is 2, and 3-3,5-dimethylphenyl, Y are phenyl and Z ABe CH 3SO 3 -3) R-W-is the 2-Trifluoromethoxyphen-l, and Y is phenyl and Z ABe CH 3SO 3 -4) R-W-is 2-methoxyl group-3-aminomethyl phenyl, and Y is phenyl and Z ABe CH 3SO 3 -5) R-W-is 2,3-dihydrobenzo [b] furans-7-base, and Y is phenyl and Z ABe CH 3SO 3 -6) R-W-is naphthalene-2-base, and Y is phenyl and Z ABe CH 3SO 3 -7) R-W-is a 4-fluoro-3-trifluoromethyl, and Y is phenyl and Z ABe CH 3SO 3 -8) R-W-is 1,2,3, and 4-naphthane-5-base, Y are phenyl and Z ABe CH 3SO 3 -9) R-W-is 1,2,3, and 4-naphthane-6-base, Y are phenyl and Z ABe CH 3SO 3 -10) R-W-is a 5-chloro-2-p-methoxy-phenyl, and Y is phenyl and Z ABe CH 3SO 3 -11) R-W-is the 2-p-methoxy-phenyl, and Y is phenyl and Z ABe CH 3SO 3 -12) R-W-is the 2-trifluoromethyl, and Y is phenyl and Z ABe CH 3SO 3 -13) R-W-is the 2-isopropyl phenyl, and Y is phenyl and Z ABe CH 3SO 3 -14) R-W-is the 2-ethylphenyl, and Y is phenyl and Z ABe CH 3SO 3 -15) R-W-is the 2-Phenoxyphenyl, and Y is phenyl and Z ABe CH 3SO 3 -16) R-W-is a benzyl, and Y is phenyl and Z ABe CH 3SO 3 -17) R-W-is 3,5-two (trifluoromethyl) phenyl, and Y is phenyl and Z ABe Cl -18) R-W-is the 2-p-methoxy-phenyl, and Y is cyclohexyl and Z ABe CH 3SO 3 -19) R-W-is a 4-fluoro-3-trifluoromethyl, and Y is cyclohexyl and Z ABe CH 3SO 3 -20) R-W-is the 2-p-methoxy-phenyl, and Y is 3,5-3,5-dimethylphenyl and Z ABe CH 3SO 3 -Perhaps 21) R-W-is the 2-p-methoxy-phenyl, and Y is naphthalene-2-base and Z ABe CH 3SO 3 -Perhaps their any other pharmacologically acceptable salt is (with regard to Z A).
The particularly preferred example of formula (I) compound is 4-phenyl-1-(3 (S)-[3; the 4-dichlorophenyl]-4-[2-(1; 2; 3; 4-tetrahydrochysene-5-naphthoyl) imidazoles-1-yl] butyl) rubane mesylate and 4-phenyl-1-(3 (R)-[3, the 4-dichlorophenyl]-4-[2-(1,2; 3,4-tetrahydrochysene-5-naphthoyl) imidazoles-1-yl] butyl) the rubane mesylate.
All formulas (I) compound can pass through formula (II) compound
Figure A9880634200151
Wherein R, R 1, Ar, W and X such as preceding formula (I) compound is defined, Z is the pharmaceutically acceptable negatively charged ion (Z that forms that suits A) leavings group and Z 1Be the leavings group that suits, with formula (III) compound prepared in reaction,
Figure A9880634200152
Wherein Y defines formula (I) compound as preceding, after the described method, (a) at Z 1When being suitable leavings group, be exchanged for pharmaceutically acceptable negatively charged ion (Z A), perhaps (b) at random, at Z ADuring for a kind of pharmaceutically acceptable negatively charged ion, be exchanged for another kind of pharmaceutically acceptable negatively charged ion.
The preferred embodiment of Z is C 1-C 4Alkane sulfonyl oxy, phenylsulfonyloxy, tolysulfonyl oxygen base, chlorine, bromine and iodine.
Z 1Example be trifluoro-methanesulfonyl oxy.
Leavings group in formula (II) compound preferably generates pharmaceutically acceptable negatively charged ion (Z/Z A), the anionresin after for example mesyloxy/methanesulfonate, so this method finishes is unnecessary.
Can in last handling process, exchange pharmaceutically acceptable negatively charged ion (with regard to Z A), for example by methanesulfonate being exchanged for chlorion with aqueous hydrochloric acid processing isolated compound or crude mixture.
Compound (II) and reaction (III) for example in the acetonitrile, at high temperature, are preferably carried out under its reflux temperature usually in The suitable solvent.
The raw material of formula (II) can prepare shown in the following reaction scheme 1.
Reaction scheme 1
Figure A9880634200161
Figure A9880634200171
Figure A9880634200181
Wherein R, R 1, Ar, W, X, Z and Z 1As preceding formula (II) compound is defined L and L 1Be the leavings group that suits, as chlorine, bromine, iodine, mesyloxy, trifluoro-methanesulfonyl oxy, phenylsulfonyloxy and tolysulfonyl oxygen base.
With reference to this paper preparation example, suitable reaction conditions, reagent and the solvent that any reactions steps shown in the reaction scheme 1 is carried out is well known to those of ordinary skill in the art.
About the final step in the reaction sequence, can adopt normal condition that formula (XV) compound is converted into formula (II) compound.For example the alcohol of formula (XV) can Z be formula (II) compound of mesyloxy, wherein Z by being converted into wherein with methylsulfonyl chloride, triethylamine and methylene dichloride processing 1Formula (II) compound that is trifluoro-methanesulfonyl oxy can be chosen wantonly in the presence of suitable acid acceptor by using trifluoromethanesulfanhydride anhydride, and the alcohol of processing formula (XV) prepares in The suitable solvent such as methylene dichloride.
Formula (XII) compound also can prepare shown in reaction scheme 2:
Reaction scheme 2
Figure A9880634200191
R wherein 1With Ar such as preceding formula (XII) compound is defined L 2And L 3Be the leavings group that suits, as preceding to L and L 1Define.
With reference to this paper preparation example, suitable reaction conditions, reagent and the solvent that any reactions steps shown in the reaction scheme 2 is carried out is well known to those of ordinary skill in the art.
Formula (XV) compound also can prepare shown in reaction scheme 3:
Reaction scheme 3
Figure A9880634200211
Figure A9880634200221
Wherein R, R 1, Ar, W and X such as preceding formula (XV) compound is defined L 4And L 5Be the leavings group that suits, as preceding to L and L 1Define, and P is the protecting group that suits.
Suitable protecting group (P) and remove the example of method can be referring to publication " protecting group in the organic synthesis (Protective Groups in Organic Synthesis) ", T.W.Greene and P.G.M.Wuts, the 2nd edition, Wiley-Interscience.The preferred embodiment of P is tetrahydropyrans-2-base, its available Amberlyst 15 (trade mark) ion exchange resin or remove with the saturated methyl alcohol of hydrogen chloride gas.
With reference to this paper preparation example, suitable reaction conditions, reagent and the solvent that any reactions steps shown in the reaction scheme 3 is carried out is well known to those of ordinary skill in the art.
Formula (XXXI) but compound also through type (XXIX) compound and formula (XXXII) compound choose wantonly at a kind of additional acid acceptor, as prepared in reaction under the existence of salt of wormwood, Wherein R and W such as preceding formula (XXXI) compound is defined.
Formula (XXXII) compound also can prepare shown in reaction scheme 4.Reaction scheme 4
Figure A9880634200241
Wherein R and W such as preceding formula (XXXII) compound is defined.
Formula (III) compound can adopt Chem.Ber., 108,3475 (1975) the middle similar approach preparations of describing.
Perhaps, formula (III) compound (wherein Y be as preceding definition to Y in formula (I) compound is defined can at random substituted cyclohexyl) but the catalytic hydrogenation preparation of through type (IIIA) compound:
Figure A9880634200251
Wherein Y is the phenyl (as above defined in the face of the definition of Y) that can replace arbitrarily.Reduction reaction can be with suitable catalyzer, as drapes over one's shoulders the rhodium aluminum oxide and carry out under nitrogen atmosphere in suitable solvent such as acetate.
The compound of formula (IIIA) can pass through Chem.Ber., the similar approach preparation of describing in 108,3475 (1975) and " organic chemistry magazine ", 22,1484 (1957).
The compound of formula (III) also can prepare shown in reaction scheme 5:
Reaction scheme 5
Y such as preceding formula (III) compound is defined wherein.
With reference to this paper preparation example, suitable reaction conditions, reagent and the solvent that any reactions steps shown in the reaction scheme 5 is carried out is well known to those of ordinary skill in the art.
The preparation of the new raw material compound that uses in all above-mentioned reactions and the preceding method all is conventional, these reactions are carried out or the suitable reagent of feedstock production and reaction conditions and the method for separating required product are well-known to those skilled in the art, referring to embodiment and the preparation example of aforementioned documents and this paper.
Formula (I) compound is to people NK 1The affinity of acceptor can adopt McLean, and S. etc. are at J.Pharm.Exp.Ther., 267, the improving one's methods of the method for describing among the 472-9 (1993) (wherein using full cell), external test their suppress [ 3H]-the P material with by expressing human NK 1The membrane-bound ability of the people IM9 clone preparation of acceptor is measured.
Formula (I) compound is to people NK 2The affinity of acceptor can by external test they with [ 3H]-NKA (neurokinin A) competition is in conjunction with by cloning by expression people NK 2The ability of the film of the Chinese hamster ovary cell preparation of acceptor is measured.In the method, method prepares clean Chinese hamster ovary cell film like that as described above, replaces IM9 cell in the preceding method with it.With film with [ 3H]-NKA cultivates (90 minutes, 25 ℃) together, uses the test compound of different concns.In the presence of 10 μ M NKA, measure non-specific binding.
The NK of formula (I) compound 1Receptor antagonist activity can be measured the ability of the contraction of the guinea pig tracheal strip that removes epithelium by their antagonism P materials of in vitro tests.Organize with guinea pig (350-600g) preparation that stupor method and avascularization are put to death.Remove the reticular tissue of excision tracheae and vertically incision, in the face of the tracheal muscle band.Remove epithelial lining with the internal surface of cotton swab friction tracheae then.Downcut the bar of about 4 sections cartilage bandwidth, and under 1g tension force, put it into 37 ℃ and charge into 95%O 2/ 5%CO 2The Krebs solution that contains (form: NaCl 118 mM, KCl 4.6mM, NaHCO 325mM, KH 2PO 41.4mM, MgSO 41.2mM, CaCl 22.5mM, glucose 11mM) organ bath in.In Krebs buffered soln, the NK of P material to existing in this tissue 2Acceptor group's latent effect can be by bringing Selection In property NK 2Receptor antagonist ± SR-48968 (1 μ M) is prevented from.In addition, add INDOMETHACIN (3 μ M) to eliminate the influence of endogenous prostanoid material.The fixed length record tissue tension changes the reaction to the accumulation adding of agonist P material.Can after 30 minutes, adopt standard Schild to analyze compound and tissue culture, the effectiveness of displacement size assessment formula (I) compound that produces according to P dosages of substance response curve.
Go the guinea pig tracheal strip goods of epithelium also can use selective N K 2Receptor stimulant [β-Ala 8] NKA (4-10)NK as shrinking agent in-vitro evaluation formula (I) compound 2Receptor antagonist activity.For this research, prepare tracheal strip as previously mentioned and put it in the organ bath, use Krebs solution composed as follows: NaCl 118 mM, KCl 4.6mM, NaHCO 325mM, KH 2PO 41.4mM, MgSO 41.2mM, CaCl 22.5mM, glucose 11mM, INDOMETHACIN 3 μ M.Can after 30 minutes, adopt standard Schild to analyze, compound and tissue culture according to [β-Ala 8] NKA (4-10)The effectiveness of the displacement size assessment compound that dose response curve produces.
Can use Maggi etc. at Br.J.Pharmacol., 101, the method among the 996-1000 (1990) is by their antagonism selective N K of in vitro tests 3Receptor stimulant senktide is to the ability of the contraction of guinea pig ileum, the NK of mensuration formula (I) compound 3Receptor antagonist activity.
For the mankind, formula (I) compound can be individually dosed, but put into practice selected pharmaceutical carrier mixing administration usually with according to route of administration and the conventional pharmacy taked.
For example, they can oral or sublingual administration, can be the tablet form that contains excipient such as starch or lactose, perhaps compound itself or with excipient blended capsule or ovum agent (ovule) form, perhaps contain elixir, solution or the form of suspension of perfume compound or tinting material.
They can be through parenteral, for example intravenously, intramuscular or subcutaneous injection administration.For parenteral admin, their best form of medication is an aseptic aqueous solution, and this solution can contain other material, for example enough salt or glucose so that solution and blood etc. ooze.
For the oral and parenteral admin of human patients, dosage level every day of formula (I) compound is 0.01～20mg/kg (but one or many dosed administration).
For once, twice or repeatedly administration on time, suitable, the tablet of this compounds or capsule will contain 1mg～1.0g active compound.In all cases, the doctor will determine the exact dosage desired of suitable individual patient, and this dosage is with age, body weight and the reactions change of particular patient.Above-mentioned dosage is giving an example of mean level (ML).Certainly exist and be suitable for higher dosage or than the various situations of low dosage scope, these include within the scope of the present invention.
Formula (I) compound also can use suitable volatilizer administration with the form of Foradil Aerolizer formoterol fumarate or aerosol spray by pressurizing vessel or atomizer easily by in the nose or inhalation, and suitable volatilizer is for example Refrigerant 12, Trichloromonofluoromethane, dichloro tetrafluoro ethane, hydro fluoroalkanes, for example 1,1,1, the 2-Tetrafluoroethane (HFA 134A[trade(brand)name]) or 1,1,1,2,3,3, and the 3-heptafluoro-propane (HFA 227EA[trade(brand)name]), carbonic acid gas or other suitable gas.Under the situation of pressurized aerosol, dose unit can be determined with the amount that discharges a metering by a valve is provided.Pressurizing vessel or atomizer can contain the solution or the suspension of active compound, for example use ethanol and the volatilizer mixture as solvent, and they can contain lubricant, for example sorbitan trioleate in addition.Capsule that uses in sucker or insufflator and medicine box (for example by the gelatin preparation) can be formulated as and contain formula (I) compound and suitable powder carrier, for example powdered mixture of lactose or starch.
Aerosol preparations is preferably designed for each dosing or " every spray " aerosol contains 20 μ g～1000 μ g formula (I) compounds to give the patient.Aerocolloidal every day, total dose was 20 μ g～20mg, and they can be administered once every day, normally repeatedly.
Perhaps, formula (I) compound can suppository or vaginal suppository form administration, and perhaps they can lotion, solution, creme, ointments or spread fertilizer over the fields powder form topical.For example they can be mixed in the creme of forming by the aqueous emulsion of polyoxyethylene glycol or whiteruss, perhaps they be mixed in the ointment of being made up of Chinese wax or paraffinum molle alba base-material and required stablizer and sanitas with the concentration of 1～10% (weight).Formula (I) compound also can use the form transdermal administration of skin patch.
Should comprise healing, alleviation or prophylactic treatment about treatment.
Therefore, the present invention also provides:
(i) contain formula (I) compound and pharmaceutically acceptable diluent or carrier pharmaceutical composition;
(ii) be used as formula (I) compound or its pharmaceutically acceptable composition of medicine;
(iii) formula (I) compound or its pharmaceutically acceptable composition are used for preparation by to a kind of tachykinin
The combination results antagonist action of acceptor or multiple tachykinin receptor is treated the medicine of disease
The purposes of thing;
Purposes (iv) as (iii), wherein antagonist action is at people NK 1And NK 2Tachykinin
Acceptor;
(v) as (iii) or purposes (iv), wherein disease is a diseases associated with inflammation, for example sacroiliitis,
Psoriasis, asthma or inflammatory bowel, central nervous system (CNS) disease, for example burnt
Consider, depressed, dementia or psychosis, stomach-intestines (GI) bitterly, as function enteropathy, allergy
Property bowel syndrome, gastroesophageal reflux, scoracratia, colitis or regional ileitis,
The disease that causes by the gram negative bacterium of helicobacter pylori or another kind of urease-positive
Sick, urogenital tract disease, for example incontinence, hyperreflexia or urocystitis, tuberculosis,
For example chronic disordered breathing tract disease, allergy, for example eczema, contact dermatitis,
Atopic dermatitis or rhinitis, anaphylactic disease, for example toxicodendron allergy, peripheral neurophaty,
For example diabetic neuropathy, neurodynia, cusalgia, painful neuropathy, burn,
Herpetic neurodynia or postherpetic neuralgia, vomiting, cough, migraine or acute and chronic
Pain;
(vi) a kind of by short of money to the combination results of a kind of tachykinin receptor or multiple tachykinin receptor
Anti-agent is used for treating the methods of treatment of human diseases, and this method comprises with significant quantity
Formula (I) compound or the described mankind of its pharmaceutically acceptable combination treatment; (vii) as (method vi), wherein antagonist action is at people NK 1And NK 2Tachykinin receptor; (viii) as (vi) or (method vii), wherein disease is a diseases associated with inflammation, sacroiliitis for example, psoriasis, asthma or inflammatory bowel, central nervous system (CNS) disease, anxiety for example, depressed, dementia or psychosis, stomach-intestines (GI) disease, as the function enteropathy, irritable bowel syndrome, gastroesophageal reflux, scoracratia, colitis or regional ileitis, the disease that causes by the gram negative bacterium of helicobacter pylori or another kind of urease-positive, the urogenital tract disease, for example incontinence, hyperreflexia or urocystitis, tuberculosis, for example chronic disordered breathing tract disease, allergy, eczema for example, contact dermatitis, atopic dermatitis or rhinitis, anaphylactic disease, toxicodendron allergy for example, peripheral neurophaty, for example diabetic neuropathy, neurodynia, cusalgia, the painful neuropathy, burn, herpetic neurodynia or postherpetic neuralgia, vomiting, cough, migraine or acute and chronic pain; (ix) formula (II), (XI), (XII), (XIII), (XIV), (XV), (XXIII), (XXX) or (XXXI) compound.
The following example has illustrated the preparation of formula of the present invention (I) compound:
Embodiment 14-phenyl-1-(3-[3,4-dichlorophenyl]-4-[2-(3, the 5-dimethylbenzoyl) imidazoles
-1-yl] butyl) the rubane mesylate
With 1-mesyloxy-3-(3; the 4-dichlorophenyl)-4-[2-(3; the 5-dimethylbenzoyl) imidazoles-1-yl]-butane (0.71g) (referring to preparation example 74) and 4-phenyl rubane (0.32g) be (referring to " organic chemistry magazine "; 22; 1484; (1957)) be dissolved in acetonitrile (10ml), this mixture heating up was refluxed 4 hours.Removal of solvent under reduced pressure, after the gained resistates is dissolved in methylene dichloride, removal of solvent under reduced pressure again.Resistates is through silica gel chromatography, and be 95: 5～85: 15 methylene dichloride with volume ratio: methyl alcohol gradient solvent wash-out obtains white foam shape product.Develop with ether then, filter and in reduced pressure at room temperature, obtain 4-phenyl-1-(3-[3,4-dichlorophenyl]-4-[2-(3, the 5-dimethylbenzoyl) imidazoles-1-yl] butyl) rubane mesylate (0.71g) white solid. 1H-NMR (CDCl 3): δ=7.62 (2H, s), 7.16-7.41 (10H, m), 7.11 (1H, s), 4.66-4.86 (2H, m), and 3.52-3.81 (7H, m), 3.32-3.47 (1H, m), 2.91-3.08 (1H, m), 2.82 (3H, s), 2.22-2.50 (14H, m) ppm. measured value: C, 61.53; H, 6.17; N, 6.03.C 36H 41C 12N 3O 4S theoretical value: C, 61.70; H, 6.18; N, 5.99%.
Embodiment 2～16
To be similar to the method for embodiment 1, be the general formula compound of feedstock production following table 1 embodiment with suitable methanesulfonates (referring to preparation example 75～84 and 86～90) and 4-phenyl rubane:
Figure A9880634200321
Table 1
Figure A9880634200331
Figure A9880634200361
Embodiment 174-phenyl-1-(3-[3,4-dichlorophenyl]-4-{2-[3,5-two (trifluoromethyl) benzoyl]
Imidazoles-1-yl } butyl) the chlorination rubane
Figure A9880634200362
With 1-mesyloxy-3-(3; the 4-dichlorophenyl)-4-{2-[3; 5-two (trifluoromethyl) benzoyl] imidazoles-1-yl }-butane (0.7g) (referring to preparation example 85) and 4-phenyl rubane (0.32g) be (referring to " organic chemistry magazine "; 22; 1484; (1957)) be dissolved in acetonitrile (10ml), this mixture heating up was refluxed 18 hours.Removal of solvent under reduced pressure, gained resistates are dissolved in methylene dichloride and use 2N aqueous hydrochloric acid washed twice.Organic phase is through anhydrous sodium sulfate drying; removal of solvent under reduced pressure; the resistates that obtains is through silica gel chromatography; it with volume ratio 95: 5～90: 10 methylene dichloride: methyl alcohol gradient solvent wash-out; obtain 4-phenyl-1-(3-[3; the 4-dichlorophenyl]-4-{2-[3,5-two (trifluoromethyl) benzoyl] imidazoles-1-yl } butyl) chlorination rubane (0.37g) white foam. 1H-NMR (CDCl 3): δ=8.69 (2H, s), 8.04 (1H, s), 7.54 (1H, s), 7.14-7.41 (9H, m), 4.76-4.96 (2H, m), 3.70-3.98 (7H, m), 3.80-3.93 (1H, m), 3.10-3.21 (1H, m), 2.49-2.62 (2H ,-m), 2.23-2.40 (6H, m) ppm. measured value: C, 56.34; H, 4.53; N, 5.55.C 35H 32Cl 3F 6N 3O1.00mol H 2O theoretical value: C, 56.12; H, 4.58; N, 5.61%.
Embodiment 184-phenyl-1-(3 (S)-[3, the 4-dichlorophenyl]-4-[2-(1,2,3,4-tetrahydrochysene-5-naphthoyl)
Imidazoles-1-yl] butyl) the rubane mesylate
Figure A9880634200371
With 1-mesyloxy-3 (S)-(3; the 4-dichlorophenyl)-4-[2-(1; 2; 3,4-tetrahydrochysene-5-naphthoyl) imidazoles-1-yl]-butane (0.82g) (referring to preparation example 105) and 4-phenyl rubane (0.35g) be (referring to " organic chemistry magazine ", 22; 1484; (1957)) be dissolved in acetonitrile (10ml), after this mixture heating up was refluxed 4 hours, it placed in room temperature spend the night.Removal of solvent under reduced pressure, gained resistates be through silica gel chromatography, and be 9: 1～8: 2 methylene dichloride with volume ratio: methyl alcohol gradient solvent wash-out obtains white foam shape product.It is dissolved in methylene dichloride, filters and remove the solvent in the filtrate, obtain 4-phenyl-1-(3 (S)-[3, the 4-dichlorophenyl]-4-[2-(1,2,3,4-tetrahydrochysene-5-naphthoyl) imidazoles-1-yl] butyl) rubane mesylate (0.7g) white powder. 1H-NMR (CDCl 3): δ=7.05-7.44 (13H, m), 4.80-4.94 (2H, m), 3.61-3.89 (7H, m), 3.38-3.71 (1H, m), 3.01-3.12 (1H, m), 2.76-2.91 (5H, m), 2.22-2.69 (10H, m), 1.63-1.86 (4H, m) ppm. measured value: C, 63.81; H, 6.20; N, 5.99.C 38H 43Cl 2N 3O 4Theoretical value: C, 64.40; H, 6.12; N, 5.93%.
Embodiment 194-phenyl-1-(3 (R)-[3, the 4-dichlorophenyl]-4-[2-(1,2,3,4-tetrahydrochysene-5-naphthoyl)
Imidazoles-1-yl] butyl) the rubane mesylate
Figure A9880634200381
Be similar to the mode of embodiment 18; with 1-mesyloxy-3 (R)-(3; the 4-dichlorophenyl)-4-[2-(1; 2; 3,4-tetrahydrochysene-5-naphthoyl) imidazoles-1-yl]-butane (referring to preparation example 106) and 4-phenyl rubane (0.36g) be (referring to " organic chemistry magazine ", 22; 1484, (1957)) be this compound of feedstock production. 1H-NMR (CDCl 3): δ=7.05-7.44 (13H, m), 4.80-4.94 (2H, m), 3.61-3.89 (7H, m), 3.38-3.71 (1H, m), 3.01-3.12 (1H, m), 2.76-2.91 (5H, m), 2.22-2.69 (10H, m), 1.63-1.86 (4H, m) ppm. measured value: C, 62.69; H, 6.07; N, 5.87.C 38H 43Cl 2N 3O 4S1.00mol H 2O theoretical value: C, 62.80; H, 6.25; N, 5.78%.
Embodiment 204-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[2-(2-anisoyl) imidazoles
-1-yl] butyl) the rubane mesylate
With 1-mesyloxy-3-(3; the 4-dichlorophenyl)-4-[2-(2-anisoyl) imidazoles-1-yl]-butane (0.59g) (referring to preparation example 84) and 4-cyclohexyl rubane (0.27g) (referring to preparation example 1) be dissolved in acetonitrile (8ml), this mixture heating up refluxed 3.5 hours.Removal of solvent under reduced pressure, gained resistates are dissolved in methylene dichloride and removal of solvent under reduced pressure once more.Resistates is through silica gel chromatography; it with volume ratio 95: 5～85: 15 methylene dichloride: methyl alcohol gradient solvent wash-out; obtain 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[2-(2-anisoyl) imidazoles-1-yl] butyl) rubane mesylate (0.69g) white foam. 1H-NMR (CDCl 3): δ=7.21-7.49 (6H, m), 6.94-7.08 (3H, m), 4.87 (1H, dd), 4.71 (1H, dd), 3.77 (3H, s), 3.33-3.70 (8H, m), 2.91-3.06 (1H, m), 2.83 (3H, s), 2.30-2.49 (2H, m), 1.60-1.89 (11H, m), 0.80-1.28 (6H, m) ppm. measured value: C, 56.76; H, 6.31; N, 5.63.C 35H 45Cl 2N 3O 5S0.5mol H 2O theoretical value: C, 56.64; H, 6.38; N, 5.66%.
Embodiment 214-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[2-(3-trifluoromethyl-4-fluoro benzoyl)
Imidazoles-1-yl] butyl) the rubane mesylate
Figure A9880634200401
With 1-mesyloxy-3-(3; the 4-dichlorophenyl)-4-[2-(3-trifluoromethyl-4-fluoro benzoyl) imidazoles-1-yl]-butane (0.77g) (referring to preparation example 80) and 4-cyclohexyl rubane (0.31g) (referring to preparation example 1) be dissolved in acetonitrile (10ml), this mixture heating up refluxed 5 hours.Removal of solvent under reduced pressure, gained resistates are dissolved in methylene dichloride and removal of solvent under reduced pressure again.Resistates is through silica gel chromatography; it with volume ratio 95: 5～80: 20 methylene dichloride: methyl alcohol gradient solvent wash-out; obtain 4-cyclohexyl-1-(3-[3,4-dichlorophenyl]-4-[2-(3-trifluoromethyl-4-fluoro benzoyl) imidazoles-1-yl] butyl) rubane mesylate (0.69g) white foam. 1H-NMR (CDCl 3): δ=8.42-8.50 (2H, m), 7.55 (1H, s), 7.22-7.32 (3H, m), and 7.11-7.20 (2H, m), 4.80-4.85 (2H, m), 3.34-3.76 (8H, m), 2.90-2.98 (1H, m), 2.85 (3H, s), and 2.30-2.50 (2H, m), 1.75-1.81 (6H, m), and 1.61-1.72 (5H, m), 1.02-1.27 (4H, m), 0.81-0.95 (2H, m) ppm. measured value: C, 56.14; H, 5.62; N, 5.70.C 35H 41Cl 2F 4N 3O 4S theoretical value: C, 56.30; H, 5.53; N, 5.63%.
Embodiment 224-(3, the 5-3,5-dimethylphenyl)-1-(3-[3,4-dichlorophenyl]-4-[2-(2-methoxybenzoyl
Base) imidazoles-1-yl] butyl) the rubane mesylate
With 1-mesyloxy-3-(3; the 4-dichlorophenyl)-4-[2-(2-anisoyl) imidazoles-1-yl]-butane (0.55g) (referring to preparation example 84) and 4-(3; the 5-3,5-dimethylphenyl) rubane (0.28g) (referring to preparation example 12) is dissolved in acetonitrile (10ml), and this mixture heating up was refluxed 2.5 hours.Removal of solvent under reduced pressure, gained resistates are dissolved in methylene dichloride and removal of solvent under reduced pressure again.Resistates is through silica gel chromatography; it with volume ratio 95: 5～90: 10 methylene dichloride: methyl alcohol gradient solvent wash-out; obtain 4-(3; the 5-3,5-dimethylphenyl)-1-(3-[3,4-dichlorophenyl]-4-[2-(2-anisoyl) imidazoles-1-yl] butyl) rubane mesylate (0.69g) white foam.
1H-NMR(CDCl 3)：δ＝7.28-7.48(5H，m)，7.23(1H，d)，6.92-7.07(3H，m)，6.88(1H，s)，
6.82(2H，s)，4.89(1H，dd)，4.71(1H，dd)，3.53-3.80(10H，m)，3.34-3.47(1H，m)，3.01-???3.12(1H，m)，2.82(3H，s)，2.42-2.51(2H，m)，2.20-2.34(12H，m)ppm.
Embodiment 23
4-(2-naphthyl)-1-(3-[3,4-dichlorophenyl]-4-[2-(2-anisoyl)
Imidazoles-1-yl] butyl) the rubane mesylate
Figure A9880634200411
With 1-mesyloxy-3-(3; the 4-dichlorophenyl)-4-[2-(2-anisoyl) imidazoles-1-yl]-butane (0.55g) (referring to preparation example 84) and 4-(2-naphthyl) rubane (0.31g) (referring to preparation example 7) be dissolved in acetonitrile (10ml), and reflux 2.5 hours.Removal of solvent under reduced pressure, gained resistates are dissolved in methylene dichloride and removal of solvent under reduced pressure again.Resistates is through silica gel chromatography; it with volume ratio 95: 5～85: 15 methylene dichloride: methyl alcohol gradient solvent wash-out; obtain 4-(2-naphthyl)-1-(3-[3,4-dichlorophenyl]-4-[2-(2-anisoyl) imidazoles-1-yl] butyl) rubane mesylate (0.65g) white foam. 1H-NMR(CDCl 3)：δ＝7.71-7.86(3H，m)，7.62(1H，s)，7.23-7.51(8H，m)，7.17(1H，s)，6.92-7.07(3H，m)，4.89(1H，dd).4.70(1H，dd)，3.61-3.86(10H，m)，3.34-3.66(1H，m)，3.03-3.16(1H，m)，2.84(3H，s)，2.30-2.55(8H，m)ppm.
Following preparation example has been described the preparation of synthetic middle some raw material that uses of compound of previous embodiment.
Preparation example 1
4-cyclohexyl rubane
4-phenyl rubane (5g) (referring to " organic chemistry magazine ", 22,1484, (1957)) is dissolved in the Glacial acetic acid (25ml), adds 5%w/w and drape over one's shoulders rhodium aluminum oxide (2g) and this mixture is descended hydrogenation 5 days at 345kPa (50psi).Make this mixture filter flocculating aids Arbaecl (trade(brand)name) short column, filter bed methanol wash.Collect filtrate and removal of solvent under reduced pressure, obtain resistates, it is soluble in water.Add 0.88 ammonia soln and transfer to pH＞10.Ethyl acetate extraction three times of this aqueous mixture merge organic layer, use the salt water washing, with anhydrous sodium sulfate drying and removal of solvent under reduced pressure, obtain 4-cyclohexyl rubane (4.7g) lightpink solid. 1H-NMR(CDCl 3)：δ＝2.75-2.96(6H，m)，1.60-1.85(5H，m)，1.06-1.45(9H，m)，1.80-1.98(3H，m)ppm.
Preparation example 2
2-(1-benzyl piepridine-4-subunit)-2-ethyl cyanacetate
Figure A9880634200422
With the heating together in toluene (200ml) of N-benzyl piepridine-4-ketone (25g), ethyl cyanacetate (16.4g), Glacial acetic acid (6ml) and ammonium acetate (2.54g), remove moisture content with Dean and Stark apparatus, heated 90 minutes.This mixture cooling is also added a certain amount of toluene (100ml) again, and this solution order water (100ml) and salt solution (100ml) washing are settled out red oily product this moment.Separate each phase, the oily product is dissolved in methylene dichloride.Combining methylbenzene and dichloromethane solution, removal of solvent under reduced pressure obtains a resistates.After resistates is dissolved in methylene dichloride, order water and saturated sodium bicarbonate aqueous solution washing, removal of solvent under reduced pressure afterwards.Crude product is through silica gel chromatography, and be 98: 2 methylene dichloride with volume ratio: methanol-eluted fractions obtains oily title compound (30.8g). 1H-NMR(CDCl 3)：δ＝7.24-7.34(5H，m)，4.22-4.32(2H，q)，3.54(2H，s)，3.12-3.16(2H，m)，2.79(2H，d)，2.66(2H，d)，2.56(2H，d)，1.32(3H，t)ppm.
Preparation example 3
2-cyano group-2-(1-benzyl-4-(2-naphthyl) piperidin-4-yl) ethyl acetate
Figure A9880634200431
2-bromonaphthalene (26g) is dissolved in anhydrous diethyl ether (100ml), under nitrogen atmosphere, 1/5 this solution is added in the mixture of the magnesium chips (3.3g) of vigorous stirring and 2-3 grain iodine crystal.Mild heat generates to cause Grignard reagent, because be difficult for keeping spontaneous backflow.Divide four addings with remaining 2-bromonaphthalene solution, behind each the interpolation, making refluxes disappears, and the final reflux of this mixture formed the organic phase of two dark colors after 1 hour.This mixture cools off in ice bath, behind the adding anhydrous tetrahydro furan (50ml), drips tetrahydrofuran (THF) (100ml) solution of 2-(1-benzyl piepridine-4-subunit)-2-ethyl cyanacetate (12g) (referring to preparation example 2).This single-phase mixture, makes it place in room temperature and spends the night after 30 minutes 0 ℃ of stirring.Twice of extracted with diethyl ether will also be used in this mixture impouring saturated aqueous ammonium chloride (450ml).Merge organic extract liquid, removal of solvent under reduced pressure obtains resistates, and this resistates is through silica gel chromatography, and be 4: 0～4: 1 methylene dichloride with volume ratio: ether gradient solvent wash-out obtains oily title compound (5.9g). 1H-NMR(CDCl 3)：δ＝7.72-7.90(4H，m)，7.46-7.57(3H，m)，7.20-7.38(5H，m)，3.85(2H，q)，3.71(1H，s)，3.37(2H，s)，2.60-2.80(4H，m)，2.15-2.40(4H，m)，0.80(3H，t)ppm.
Preparation example 4
2-(1-benzyl-4-(2-naphthyl) piperidin-4-yl) ethyl acetate
Figure A9880634200441
Water (30ml) solution of potassium hydroxide (10g) is added in ethanol (40ml) solution of 2-cyano group-2-(1-benzyl-4-(2-naphthyl) piperidin-4-yl) ethyl acetate (5.9g) (referring to preparation example 3), after stirred overnight at room temperature, heating is until forming transparent solution in vapor bath with gained suspension.This solution is divided into two parts puts into microwave container, microwave treatment is 5 hours under 690kPa (100psi)/100% intensity (power).Then solution is merged, removal of solvent under reduced pressure, resistates and methylbenzene azeotropic are removed all remaining moisture content for 4 times.Resistates is dissolved in the ethanol (250ml), cools off in ice bath, this solution is saturated with hydrogen chloride gas, has precipitation to form therebetween.This mixture being placed 3 days in room temperature, filtered and solvent in the filtrate is removed in decompression, obtain resistates, through silica gel chromatography, is 98: 2～96: 4 methylene dichloride with volume ratio: methyl alcohol gradient solvent wash-out obtains the hydrochloride of title compound.This hydrochloride is assigned between methylene dichloride and the saturated aqueous sodium carbonate, separates organic phase, through anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains oily title compound (3.6g). 1H-NMR(CDCl 3)：δ＝7.70-7.85(4H，m)，7.40-7.52(3H，m)，7.20-7.32(5H，m)，3.78(2H，q)，3.41(2H，s)，2.58-2.70(4H，m)，2.30-2.50(4H，m)，2.10-2.20(2H，m)，0.84(3H，t)ppm.
Preparation example 5
4-(2-naphthyl)-4-(2-hydroxyethyl)-N-benzyl piepridine
Figure A9880634200451
2-(1-benzyl-4-(2-naphthyl) piperidin-4-yl) ethyl acetate (5.8g) (referring to preparation example 4) is dissolved in the anhydrous diethyl ether (100ml), and cooling and gradation add lithium aluminum hydride (0.57g) in ice bath.This mixture after 30 minutes, is added entry (0.8ml) in stirring at room carefully, add 2N aqueous sodium hydroxide solution (0.8ml) then, add entry (1.6ml) afterwards again.This mixture stirring after 20 minutes, is removed by filter the particulate state precipitation.The solvent that decompression is removed in the filtrate obtains a solid, and it is dissolved in methylene dichloride, and through anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains 4-(2-naphthyl)-4-(2-hydroxyethyl)-N-benzyl piepridine (2.2g) white solid once more.
The particulate state precipitation is developed and filtered with methylene dichloride.The filtrate water washing with anhydrous sodium sulfate drying and removal of solvent under reduced pressure, obtains second crowd of 4-(2-naphthyl)-4-(2-hydroxyethyl)-N-benzyl piepridine (2.7g) white solid.
1H-NMR(CDCl 3)：δ＝7.75-7.86(3H，m)，7.70(1H，s)，7.43-7.50(3H，m)，7.20-7.35
(5H，m)，3.35-3.45(4H，m)，2.60-2.70(2H，m)，2.25-2.40(4H，m)，1.92-2.04(4H，m)，
0.90(1H，br，s)ppm.
Preparation example 6
4-(2-naphthyl)-N-benzyl rubane 4-toluenesulfonate
Figure A9880634200452
4-(2-naphthyl)-4-(2-hydroxyethyl)-N-benzyl piepridine (4.9g) (referring to preparation example 5) is dissolved in pyridine (30ml), in ice bath, after the cooling, adds 4-Methyl benzenesulfonyl chlorine (3.0g).Make this mixture 0 ℃ place 16 hours after, removal of solvent under reduced pressure.Resistates is suspended in the 10%w/w wet chemical (120ml), with toluene extraction (2 * 130ml).The organic phase that merges after dry 10 minutes, is filtered through Anhydrous potassium carbonate with the washing of 10%w/w wet chemical.Collect filtrate, under reduced pressure make volume reduce to about 60ml, obtain a suspension., it is placed in room temperature spend the night after 6 hours 90 ℃ of heating then, obtain precipitation, filter.With toluene and ether washing, drying obtains 4-(2-naphthyl)-N-benzyl rubane 4-toluenesulfonate (3.5g) white solid to this precipitation in proper order. 1H-NMR(CDCl 3)：δ＝7.90(2H，d)，7.78(3H，m)，7.30-7.65(9H，m)，7.16(2H，d)，4.89(2H，s)，3.80-3.95(6H，m)，2.31(3H，s)，2.13-2.29(6H，m)ppm.
Preparation example 7
4-(2-naphthyl) rubane
Figure A9880634200461
4-(2-naphthyl)-N-benzyl rubane 4-toluenesulfonate (3.5g) (referring to preparation example 6) is dissolved in methyl alcohol (35ml), adds 10%w/w palladium on carbon (0.5g), make this mixture the following hydrogenation of 345kPa (50psi) 40 hours.Make this mixture filter flocculating aids Arbacel (trade(brand)name) short column then, filtrate decompression is removed and is desolvated, and obtains a resistates.This resistates is assigned between ether and the 1N aqueous sodium hydroxide solution.Separate two-phase, twice of extracted with diethyl ether of water.Merge organic phase and removal of solvent under reduced pressure.The gained resistates is dissolved in ethyl acetate, after this solution is used 0.88 ammonia soln and salt water washing in proper order, through anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains 4-(2-naphthyl) rubane (1.56g) solid once more. 1H-NMR(CDCl 3)：δ＝7.80(3H，d)，7.63(1H，s)，7.40-7.52(3H，m)，3.00-3.15(6H，m)，1.82-1.96(6H，m)ppm.
Preparation example 8
2-cyano group-2-(1-benzyl-4-(3, the 5-3,5-dimethylphenyl) piperidin-4-yl) ethyl acetate
With 1,3-dimethyl-5-bromobenzene (15.6g) is dissolved in the anhydrous diethyl ether (60ml), under nitrogen atmosphere it is added in the mixture of the magnesium chips (2.2g) of vigorous stirring and 2-3 grain iodine crystal.Mild heat generates to cause Grignard reagent, in case spontaneous backflow is disappeared, this mixture reheat is refluxed 30 minutes.This mixture is cooled off in ice bath, with anhydrous tetrahydro furan (80ml) solution that added 2-(1-benzyl piepridine-4-subunit)-2-ethyl cyanacetate (8.0g) (referring to preparation example 2) in 20 minutes.This mixture after 15 minutes, makes it place 3 days in room temperature 0 ℃ of stirring.With in this mixture impouring saturated aqueous ammonium chloride (300ml), use twice of extracted with diethyl ether then.Merge organic extract liquid, removal of solvent under reduced pressure obtains resistates, and through silica gel chromatography, be 3: 0～3: 1 methylene dichloride with volume ratio: ether gradient solvent wash-out obtains oily title compound (4.7g). 1H-NMR(CDCl 3)：δ＝7.20-7.35(5H，m)，6.91(3H，s)，3.94(2H，q)，3.61(1H，s)，3.40(2H，s)，2.40-2.70(4H，m)，2.30(6H，s)，2.10-2.22(4H，m)，1.00(3H，t)ppm.
Preparation example 9
2-(1-benzyl-4-(3, the 5-3,5-dimethylphenyl) piperidin-4-yl) ethyl acetate
Figure A9880634200472
Water (20ml) solution of potassium hydroxide (3.4g) is added to 2-cyano group-2-(1-benzyl-4-(3, the 5-3,5-dimethylphenyl) piperidin-4-yl) in ethanol (24ml) solution of ethyl acetate (4.7g) (referring to preparation example 8), with this compound microwave treatment 2.5 hours under 345kPa (100psi)/100% intensity.Removal of solvent under reduced pressure, resistates and methylbenzene azeotropic are removed remaining moisture.Resistates is dissolved in ethanol (100ml), in ice bath, cools off, make this solution saturated with hydrogen chloride gas.This mixture uses hydrogen chloride gas saturated after the room temperature placement is spent the night again, places afterwards 24 hours again.This solution is filtered, and filtrate decompression is removed and is desolvated, and obtains resistates, and it is dissolved in saturated aqueous sodium carbonate and uses twice of dichloromethane extraction.Merge organic phase, through anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains resistates, and through silica gel chromatography, be 97: 3～90: 10 methylene dichloride with volume ratio: methyl alcohol gradient solvent wash-out obtains oily title compound (2.0g). 1H-NMR(CDCl 3)：δ＝7.20-7.35(5H，m)，6.90(2H，5)，6.82(1H，s)，3.80-3.90(2H，q)，3.43(2H，s)，2.50-2.63(4H，m)，2.20-2.40(10H，m)，1.92-2.08(2H，m)，0.95-1.03(3H，t)ppm.
Preparation example 10
4-(3.5-3,5-dimethylphenyl)-4-(2-hydroxyethyl)-N-benzyl piepridine
Figure A9880634200481
2-(1-benzyl-4-(3, the 5-3,5-dimethylphenyl) piperidin-4-yl) ethyl acetate (2.0g) (referring to preparation example 9) is dissolved in the anhydrous diethyl ether (50ml), and cooling and gradation add lithium aluminum hydride (0.21g) in ice bath.This mixture after 45 minutes, is added entry (0.3ml) in stirring at room carefully, add 2N aqueous sodium hydroxide solution (0.3ml) then, add entry (0.6ml) afterwards again.After this mixture stirred 20 minutes, remove by filter the particulate state precipitation and wash with ether.Filtrate decompression is removed to desolvate and is obtained a solid, and it is dissolved in methylene dichloride, and through anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains oily 4-(3, the 5-3,5-dimethylphenyl)-4-(2-hydroxyethyl)-N-benzyl piepridine (1.67g) once more. 1H-NMR(CDCl 3)：δ＝7.20-7.35(5H，m)，6.90(2H，s)，6.83(1H，s)，3.32-3.43(4H，m)，2.54-2.64(2H，m)，2.13-2.37(11H，m).1.8-1.90(4H，m)ppm.
Preparation example 11
4-(3, the 5-3,5-dimethylphenyl)-N-benzyl rubane 4-toluenesulfonate
4-(3, the 5-3,5-dimethylphenyl)-4-(2-hydroxyethyl)-N-benzyl piepridine (1.6g) (referring to preparation example 10) is dissolved in pyridine (10ml), in ice bath, after the cooling, adds 4-Methyl benzenesulfonyl chlorine (1.0g) 4 times with 10 minutes branches.Make this mixture 0 ℃ place 16 hours after, removal of solvent under reduced pressure.Resistates is suspended in the 10%w/w wet chemical (30ml), with toluene extraction (50ml).Organic phase, is filtered after the Anhydrous potassium carbonate drying with the washing of 10%w/w wet chemical.Collect filtrate, decompression makes volume reduce to about 12ml, obtains a suspension.90 ℃ of heating 3 hours, it is cooled off in room temperature then, when volume reduced to about 5ml, product began to precipitate from solution.Add ether (30ml), filtering-depositing, with the ether washing, drying obtains 4-(3, the 5-3,5-dimethylphenyl)-N-benzyl rubane 4-toluenesulfonate (1.59g) white solid. 1H-NMR(CDCl 3)：δ＝7.96(2H，d)，7.58(2H，d)，7.30-7.40(3H，m)，7.16(2H，d)，6.96(1H，s)，6.75(2H，s)，4.86(2H，d)，3.72-3.82(6H，m)，2.34(3H，s)，2.25(6H，s)，2.05-2.12(6H，m)ppm.
Preparation example 12
4-(3, the 5-3,5-dimethylphenyl) rubane
Figure A9880634200492
4-(3, the 5-3,5-dimethylphenyl)-N-benzyl rubane 4-toluenesulfonate (1.4g) (referring to preparation example 11) is dissolved in methyl alcohol (14ml), adds 10%w/w palladium on carbon (0.2g), make this mixture the following hydrogenation of 345kPa (50psi) 40 hours.Make this mixture filter flocculating aids Arbacel (trade(brand)name) short column then, filtrate decompression is removed and is desolvated, and obtains a resistates.This resistates is assigned between ether and the 1N aqueous sodium hydroxide solution.Separate two-phase, twice of extracted with diethyl ether of water.Merge organic phase and removal of solvent under reduced pressure.The gained resistates is dissolved in ethyl acetate, after this solution is used the salt water washing, through anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains 4-(3, the 5-3,5-dimethylphenyl) rubane (0.59g) white solid once more. 1H-NMR(CDCl 3)：δ＝6.89(2H，s)，6.83(1H，s)，2.95-3.05(6H，m)，2.33(6H，s)，1.70-1.81(6H，m)ppm.
Preparation example 13
2-(3, the 4-dichlorophenyl)-3-(1,3-dioxolane-2-yl) propionitrile
Figure A9880634200501
Under nitrogen atmosphere, sodium hydride (60%w/w mineral oil dispersion) (4.73g) is suspended in the tetrahydrofuran (THF) (70ml), and this mixture is cooled off in ice bath.Drip 3 with 35 minutes, tetrahydrofuran (THF) (80ml) solution of 4-dichlorophenyl acetonitrile (20g) makes this mixture be warming to room temperature and stirred 16 hours.Add 2-brooethyl-1,3-dioxolane (19.71g) and tetrabutylammonium iodide (2g) reflux the gained mixture heating up 4 hours.With the cooling of this mixture and be assigned between ethyl acetate and the water.Separate organic layer and use the salt water washing.Organic solvent is removed in decompression, obtains a brown oil, and through silica gel chromatography, be 80: 20 ethyl acetate with volume ratio: the hexane wash-out obtains an orange flowable oily product.Then this oil is dissolved in methyl alcohol, in ice, cools off, form precipitation, filter,, obtain 2-(3, the 4-dichlorophenyl)-3-(1,3-dioxolane-2-yl) propionitrile (15.8g) white solid with methanol wash and drying under reduced pressure. 1H-NMR(CDCl 3)：δ＝7.40-7.50(2H，m)，7.20-7.25(1H，dd)，4.95(1H，dd)，3.82-4.05(5H，m)，2.30-2.40(1H，m)，2.05-2.15(1H，m)ppm.
Preparation example 14
2-(3, the 4-dichlorophenyl)-3-(1,3-dioxolane-2-yl) propane-1-aldehyde
Figure A9880634200511
Under nitrogen atmosphere, be suspended in 2-(3, the 4-dichlorophenyl)-3-(1,3-dioxolane-2-yl) propionitrile (64g) (referring to preparation example 13) in the dry toluene (500ml) and be cooled to-70 ℃.Add diisobutyl aluminium hydride (200ml 1.5M toluene solution) with 50 minutes then, obtain clear solution this moment.Make this mixture-70 ℃ of restir 30 minutes, make it be warming to-20 ℃ lentamente then.After adding entry (24ml) (thermopositive reaction) carefully, in mixture impouring 15% (weight) aqueous citric acid solution (1800ml).Add toluene (100ml) and with this mixture vigorous stirring 1 hour.The gained emulsion is filtered flocculating aids Arbacel (trade(brand)name) short column, obtain transparent two-phase, separate.Organic phase salt water washing through anhydrous sodium sulfate drying and removal of solvent under reduced pressure, obtains 2-(3, the 4-dichlorophenyl)-3-(1,3-dioxolane-2-yl) propane-1-aldehyde (53.5g) of yellow oily. 1H-NMR(CDCl 3)：δ＝9.90(1H，s)，7.10-7.50(3H，m)，4.89(1H，t)，3.704.00(5H，m)，1.45-1.55(1H，m)，2.20-2.10(1H，m)ppm.
Preparation example 15
2-(3, the 4-dichlorophenyl)-3-(1,3-dioxolane-2-yl) propane-1-alcohol
Figure A9880634200512
In ethanol (300ml) solution that sodium borohydride (5g) was added at twice in 40 minutes ice-cooled 2-(3, the 4-dichlorophenyl)-3-(1,3-dioxolane-2-yl) propane-1-aldehyde (53.5g) (referring to preparation example 14).This mixture restir is after 30 minutes, and removal of solvent under reduced pressure obtains a resistates.This resistates is suspended in the water (200ml), is cooled to 0 ℃, the Glacial acetic acid acidifying (pH＜6) of this mixture.Add methylene dichloride, add solid sodium carbonate alkalization water (pH＞8) afterwards.Add a certain amount of methylene dichloride (200ml) again, with organic phase and aqueous phase separation.Water is further used dichloromethane extraction (200ml).Merge organic phase, use the salt water washing,, obtain 2-(3, the 4-dichlorophenyl)-3-(1,3-dioxolane-2-yl) propane-1-alcohol (54.6g) of yellow oily through anhydrous sodium sulfate drying and removal of solvent under reduced pressure. 1H-NMR(CDCl 3)：δ＝7.30-7.45(2H，m)，7.09(1H，dd)，4.79(1H，t)，3.70-4.00(6H，m)，2.97-3.08(1H，m)，1.96-2.09(3H，m)ppm.
Preparation example 16
1-mesyloxy-2-(3, the 4-dichlorophenyl)-3-(1,3-dioxolane-2-yl) propane
In the ice-cooled solution of methylene dichloride (100ml) that methylsulfonyl chloride (5.5g) was added in 10 minutes 2-(3, the 4-dichlorophenyl)-3-(1,3-dioxolane-2-yl) propane-1-alcohol (12g) (referring to preparation example 15) and triethylamine (5.7g).Stir this mixture after 30 minutes, add methylene dichloride (50ml) again.This solution order water (3 * 50ml) and after salt solution (50ml) washs, through anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains yellow oily 1-mesyloxy-2-(3, the 4-dichlorophenyl)-3-(1,3-dioxolane-2-yl) propane (15.6g), and this product is through placing after fixing. 1H-NMR(CDCl 3)：δ＝7.41(1H，d)，7.34(1H，d)，7.10(1H，dd)，4.75(1H，t)，4.26-4.43(2H，m)，3.90-4.00(2H，m)，3.80-3.87(2H，m)，3.30(1H，m)，2.90(3H，s)，2.00-2.10(2H，m)ppm.
Preparation example 17
1-(imidazoles-1-yl)-2-(3, the 4-dichlorophenyl)-3-(1,3-dioxolane-2-yl) propane
Figure A9880634200531
1-mesyloxy-2-(3, the 4-dichlorophenyl)-3-(1,3-dioxolane-2-yl) propane (15.5g) (referring to preparation example 16) and imidazoles (9g) are dissolved in the anhydrous acetonitrile (100ml), this mixture heating up was refluxed 90 hours.Removal of solvent under reduced pressure, resistates are dissolved in methylene dichloride (100ml) and removal of solvent under reduced pressure once more.Resistates is dissolved in methylene dichloride (300ml) again and also washs to guarantee that water pH reaches 14 with the aqueous sodium carbonate of capacity.Separate two-phase, water dichloromethane extraction (100ml).Merge organic phase, removal of solvent under reduced pressure, obtain a resistates, through silica gel chromatography, be 99: 1～95: 5 methylene dichloride with volume ratio: methyl alcohol gradient solvent wash-out obtains orange buttery 1-(imidazoles-1-yl)-2-(3, the 4-dichlorophenyl)-3-(1,3-dioxolane-2-yl) propane (11.1g). 1H-NMR(CDCl 3)：δ＝6.95-7.40(4H，m)，6.85(1H，dd)，6.69(1H，s)，4.69(1H，m)，4.15-4.25(1H，m)，3.70-4.10(5H，m)，3.15-3.25(1H，m)，1.90-2.10(2H，m)ppm.
Preparation example 18
3-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-aldehyde
5N aqueous hydrochloric acid (100ml) is added in tetrahydrofuran (THF) (100ml) solution of ice-cooled 1-(imidazoles-1-yl)-2-(3, the 4-dichlorophenyl)-3-(1,3-dioxolane-2-yl) propane (11g) (referring to preparation example 17).After making this mixture be warming to room temperature lentamente, placed again 24 hours.Tetrahydrofuran (THF) is removed in decompression, and acidity is used dichloromethane extraction (2 * 100ml) mutually.Merge organic phase, use the salt water washing, through anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains crude product, and through silica gel chromatography, be 97.5: 2.5～95: 5 methylene dichloride with volume ratio: methyl alcohol gradient solvent wash-out obtains thickness buttery 3-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-aldehyde (4.4g). 1H-NMR(CDCl 3)：δ＝9.70(1H，s)，7.38(1H，d)，7.20-7.30(2H，m)，7.01(1H，s)，6.89(1H，dd)，6.71(1H，s)，4.00-4.22(2H，m)，3.60(1H，m)，2.72-2.92(2H，m)ppm.
Preparation example 19
3-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-alcohol
Figure A9880634200541
Three times sodium borohydride (0.52g) is added in ethanol (25ml) solution of ice-cooled 3-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-aldehyde (3.3g) (referring to preparation example 18) with 5 minutes branches.After 1 hour, removal of solvent under reduced pressure obtains a resistates with this mixture restir.This resistates is suspended in the water (50ml), be cooled to 0 ℃ after, at first be acidified to pH1 with the 2N aqueous hydrochloric acid, add solid sodium carbonate then and be basified to pH14, use ethyl acetate extraction (3 * 200ml) subsequently.Merge organic phase, through anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains 3-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-alcohol (2.84g) emulsus solid. 1H-NMR(CDCl 3)：δ＝7.35(1H，d)，7.15-7.30(2H，m)，6.95(1H，s)，6.89(1H，d)，6.70(1H，s)，4.00-4.25(2H，m)，3.60-3.70(1H，m)，3.40-3.50(1H，m)，3.15-3.30(1H，m)，2.10(1H，br.s)，1.75-2.00(2H，m)ppm.
Preparation example 20
4-cyano group-4-(3, the 4-dichlorophenyl) but-1-ene
Under nitrogen atmosphere, with 3,4-dichlorophenyl acetonitrile (80g) is dissolved in the anhydrous tetrahydro furan (800ml), is cooled to-70 ℃, adds lithium diisopropylamine (320ml 1.5M cyclohexane solution).This mixture-70 ℃ stir 30 minutes after, with adding allyl bromide 98 (63g) in 15 minutes also with this mixture restir 30 minutes.Add 2N aqueous hydrochloric acid (600ml) then, twice of extracted with diethyl ether of this mixture.Merge organic extract liquid and removal of solvent under reduced pressure.The gained resistates is dissolved in the methylene dichloride, through anhydrous sodium sulfate drying and removal of solvent under reduced pressure, obtains the mobile reddish oil.Through silica gel chromatography, be 4: 1 hexane with volume ratio: the methylene dichloride wash-out obtains oily 4-cyano group-4-(3, the 4-dichlorophenyl) but-1-ene (94.8g). 1H-NMR(CDCl 3)：δ＝7.40-7.51(2H，m)，7.14-7.21(1H，m)，5.70-5.95(1H，m)，5.13-5.27(2H，m)，3.84(1H，t)，2.56-2.70(2H，m)ppm.
Preparation example 21
4-(3, the 4-dichlorophenyl)-4-formyl radical but-1-ene
Figure A9880634200551
Under nitrogen atmosphere, be dissolved in 4-cyano group-4-(3, the 4-dichlorophenyl) but-1-enes (13g) (referring to preparation example 20) in the dry toluene (100ml) and be cooled to-70 ℃.Add diisobutyl aluminium hydride (50ml 1.5M toluene solution) and this mixture was stirred 30 minutes at-70 ℃ in this solution with 30 minutes, be warming to-10 ℃ then lentamente.After adding entry (6ml) (thermopositive reaction) carefully, in its impouring 15% (weight) aqueous citric acid solution (500ml), added toluene (300ml) and vigorous stirring afterwards 30 minutes.Separate two-phase, organic phase salt water washing through anhydrous sodium sulfate drying and removal of solvent under reduced pressure, obtains oily 4-(3, the 4-dichlorophenyl)-4-formyl radical but-1-ene (14g). 1H-NMR(CDCl 3)：δ＝9.68(1H，s)，7.48(1H，d)，7.31(1H，s)，7.03(1H，d)，5.61-5.77(1H，m)，4.94-5.13(2H，m)，3.56-3.65(1H，m)，2.77-2.91(1H，m)，2.40-2.54(1H，m)ppm.
Preparation example 22
4-(3, the 4-dichlorophenyl)-5-hydroxyl penta-1-alkene
Figure A9880634200561
With 10 minutes sodium borohydride (2.2g) is divided in ethanol (100ml) solution that is added to ice-cooled 4-(3, the 4-dichlorophenyl)-4-formyl radical but-1-ene (13g) (referring to preparation example 21) for four times.This mixture restir is after 30 minutes, and removal of solvent under reduced pressure obtains a resistates.This resistates is suspended in the water (50ml), is cooled to 0 ℃, the 2N aqueous hydrochloric acid acidifying (pH＜6) of this mixture.Dichloromethane extraction three times of this mixture merge organic phase, and removal of solvent under reduced pressure.Add methylene dichloride (200ml) then, stir and filter, filtrate decompression is removed and is desolvated, and obtains an oily matter.Chromatogram is used the methylene dichloride wash-out after filtration, obtains orange buttery 4-(3, the 4-dichlorophenyl)-5-hydroxyl penta-1-alkene (7g). 1H-NMR(CDCl 3)：δ＝7.24-7.45(2H，m)，7.06(1H，dd)，5.61-5.75(1H，m)，4.96-5.10(2H，m)，3.70-3.90(2H，m)，2.80-2.91(1H，m)，2.30-2.55(2H，m)，1.32(1H，t)ppm.
Preparation example 23
4-(3, the 4-dichlorophenyl)-5-(mesyloxy) penta-1-alkene
Figure A9880634200562
Be added in methylene dichloride (50ml) solution of ice-cooled 4-(3, the 4-dichlorophenyl)-5-hydroxyl penta-1-alkene (4.3g) (referring to preparation example 22) and triethylamine (2.5g) with the 10 minutes methylene dichloride with methylsulfonyl chloride (2.3g) (10ml) solution.This mixture restir is after 30 minutes, the order water (3 * 25ml) and salt solution (25ml) wash, then through anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains oily 4-(3, the 4-dichlorophenyl)-5-(mesyloxy) penta-1-alkene (5.4g). 1H-NMR(CDCl 3)：δ＝7.42(1H，d)，7.30(1H，s)，7.04(1H，dd)，5.56-5.72(1H，m)，5.01-5.10(2H，m)，4.22-4.39(2H，m)，3.05-3.15(1H，m)，2.88(3H，s)，2.33-2.60(2H，m)ppm.
Preparation example 24
4-(3, the 4-dichlorophenyl)-5-(imidazoles-1-yl) penta-1-alkene (and hydrochloride)
Figure A9880634200571
4-(3, the 4-dichlorophenyl)-5-(mesyloxy) penta-1-alkene (5.4g) (referring to preparation example 23) and imidazoles (3.6g) are dissolved in the anhydrous acetonitrile (40ml) also with this mixture heating up backflow 100 hours.Removal of solvent under reduced pressure, resistates are dissolved in methylene dichloride and removal of solvent under reduced pressure once more.Resistates is dissolved in methylene dichloride (100ml) and also washs to guarantee that water pH reaches 14 with the aqueous sodium carbonate of capacity, separates two-phase, water dichloromethane extraction (100ml).Merge organic phase, removal of solvent under reduced pressure obtains resistates, through silica gel chromatography, is 100: 0～98: 2 methylene dichloride with volume ratio: methyl alcohol gradient solvent wash-out, obtain orange buttery 4-(3, the 4-dichlorophenyl)-5-(imidazoles-1-yl) penta-1-alkene (3.45g). 1H-NMR(CDCl 3)：δ＝7.35(1H，d)，7.15-7.30(2H，m)，6.99(1H，s)，6.84(1H，d)，6.69(1H，s)，5.55-5.70(1H，m)，5.07(2H，d)，3.95-4.22(2H，m)，2.95-3.10(1H，m)，2.32-2.45(2H，m)ppm.
The preparation of hydrochloride: by free alkali is dissolved in methylene dichloride, handle this solution,, obtain spumescence 4-(3, the 4-dichlorophenyl)-5-(imidazoles-1-yl) penta-1-pinene hyhrochloride through removal of solvent under reduced pressure with hydrogen chloride gas.
Preparation example 25
(the another kind of method of preparation example 18)
3-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-aldehyde
4-(3, the 4-dichlorophenyl)-5-(imidazoles-1-yl) penta-1-pinene hyhrochloride (3.6g) (referring to preparation example 24) is dissolved in the mixed solution of acetonitrile (50ml) and water (20ml), adds perosmic anhydride (4ml 0.05M toluene solution).This mixture stirred 30 minutes, added sodium periodate (5.3g) and continue to stir 2 hours.Add another part acetonitrile (20ml) and continue stirring after 16 hours, organic solvent is removed in decompression, obtains an aq suspension.Add solid sodium carbonate and alkalize this suspension to pH＞7.This mixture dichloromethane extraction, organic phase is through anhydrous sodium sulfate drying and removal of solvent under reduced pressure, obtain dark oily matter, through silica gel chromatography, it with volume ratio 98: 2～92.5: 7.5 methylene dichloride: methyl alcohol gradient solvent wash-out, obtain colourless thickness buttery 3-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-aldehyde (2.28g). 1H-NMR(CDCl 3)：δ＝9.70(1H，s)，7.38(1H，d)，7.20-7.30(2H，m)，7.01(1H，s)，6.89(1H，dd)，6.71(1H，s)，4.00-4.22(2H，m)，3.60(1H，m)，2.72-2.92(2H，m)ppm.
Preparation example 26
2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butyronitrile
Figure A9880634200582
Under 0 ℃ and nitrogen atmosphere, (19.24g) and in the mixture of anhydrous tetrahydro furan (450ml) dripped 3 with 40 minutes toward sodium hydride (60%w/w mineral oil dispersion), anhydrous tetrahydro furan (450ml) solution of 4-dichlorophenyl acetonitrile (89.5g).Through after 30 minutes, add anhydrous tetrahydro furan (100ml) solution of 2-(2-bromine oxethyl) tetrahydropyrans (100g) again.Make this mixture be warming to room temperature, stirred then 14 hours.Add 30%w/w aqueous ammonium chloride solution (500ml), with extracted with diethyl ether (2 * 400ml).Merge organic extract liquid, wash with water (2 * 400ml), through anhydrous magnesium sulfate drying and removal of solvent under reduced pressure.Resistates is through silica gel chromatography, is 1: 9～1: 1 ether with volume ratio: the hexane gradient solvent elution obtains 2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base)-butyronitrile (51g) of buttery non-enantiomer mixture form. 1H-NMR (CDCl 3) (mixtures of 2 diastereomers): δ=7.25-7.50 (2H, m), 7.20-7.25 (1H, m), 4.50-4.60 (1H, m), 4.00-4.10 (1H, m), 2.80-2.95 (2H, m), 2.40-2.65 (2H, m), and 2.05-2.30 (2H, m), 1.50-1.90 (6H, m) ppm.
Preparation example 27
2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butane-1-aldehyde
Figure A9880634200591
Under nitrogen atmosphere, 2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butyronitrile (20.2g) (referring to preparation example 26) is dissolved in the dry toluene (300ml), be cooled to-78 ℃.Drip diisobutyl aluminium hydride (85.6ml 1.0M toluene solution) then.This mixture after 1.5 hours, makes it slowly be warming to-40 ℃-78 ℃ of stirrings.Add entry (100ml) and saturated aqueous ammonium chloride (50ml) (thermopositive reaction) carefully, make this mixture be warming to 10 ℃ after, add entry (100ml) and saturated aqueous ammonium chloride (50ml) again.Add 10%w/w Rochelle salt (Rochelle salt) aqueous solution (400ml), this mixture extracted with diethyl ether.Organic phase obtains crude product through anhydrous sodium sulfate drying and removal of solvent under reduced pressure.This crude product is through silica gel chromatography, is 98: 2 methylene dichloride with volume ratio: methanol-eluted fractions obtains 2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butane-1-aldehyde (17.02g) of the non-enantiomer mixture form of yellow oily. 1H-NMR (CDCl 3) (mixtures of 2 diastereomers): δ=9.70 (1H, s), 7.44 (1H, d), 7.32 (1H, m), 7.06 (1H, m), 4.55 (0.5H, t), 4.46 (0.5H, t), 3.20-3.90 (6H, m), 2.35-2.50 (1H, m), 1.45-2.00 (6H, m) ppm.
Preparation example 28
2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butane-1-alcohol
Figure A9880634200601
Sodium borohydride (2.03g) gradation is added in 2-propyl alcohol (250ml) solution of 2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butane-1-aldehyde (17.02g) (referring to preparation example 27).This mixture after stirred overnight at room temperature, is added Glacial acetic acid (4ml) carefully, add entry (2ml) then.Removal of solvent under reduced pressure obtains resistates, and it is dissolved in methylene dichloride and order water, dilute aqueous solution of sodium bicarbonate and salt water washing.This solution behind anhydrous sodium sulfate drying, removal of solvent under reduced pressure.Crude product is through silica gel chromatography, is 1: 1 ethyl acetate with volume ratio: the hexane wash-out obtains 2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butane-1-alcohol (14.7g) of the non-enantiomer mixture form of colorless oil. 1H-NMR (CDCl 3) (mixtures of 2 diastereomers): δ=7.30-7.40 (2H, m), 7.09 (1H, d), 4.55 (0.5H, t), 4.46 (0.5H, t), 3.24-3.82 (6H, m), 2.90-3.00 (1H, m), 1.45-2.10 (9H, m) ppm.
Preparation example 29
1-mesyloxy-2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butane
Under nitrogen atmosphere, methylsulfonyl chloride (2.4ml) is added drop-wise in ice-cooled 2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butane-1-alcohol (8.13g) (referring to preparation example 28) and the solution of triethylamine (5.32ml) in methylene dichloride (100ml).This mixture 0 ℃ stir 10 minutes after, stirring at room 90 minutes, wash with water then twice.Separate organic phase,, obtain crude product through anhydrous sodium sulfate drying and removal of solvent under reduced pressure.Through silica gel chromatography, be 95: 5 methylene dichloride with volume ratio: the ether wash-out obtains 1-mesyloxy-2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butane (8.85g) of the non-enantiomer mixture form of yellow oily. 1H-NMR (CDCl 3) (mixtures of 2 diastereomers): δ=7.42 (1H, d), 7.32 (1H, dd), 7.09 (1H, m), 4.30-4.50 (3H, m), 3.20-3.80 (5H, m), 2.89 (3H, s), 2.05-2.15 (1H, m), 1.50-1.95 (7H, m) ppm.
Preparation example 30
1-(imidazoles-1-yl)-2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butane
Figure A9880634200611
With 1-mesyloxy-2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butane (10g) (referring to preparation example 29), imidazoles (2.07g) with salt of wormwood (7.65g) is dissolved in the anhydrous acetonitrile (50ml) and reflux 3 days under nitrogen atmosphere.Organic solvent is removed in decompression, and the gained aq suspension is assigned between methylene dichloride and the water.Separate organic phase, order water and salt water washing are through the anhydrous sodium sulfate drying and the product solvent that reduces pressure.Crude product is through silica gel chromatography, is 95: 5 methylene dichloride with volume ratio: methanol-eluted fractions obtains 1-(imidazoles-1-yl)-2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butane (3g) of buttery non-enantiomer mixture form. 1H-NMR (CDCl 3) (mixtures of 2 diastereomers): δ=7.35 (1H, d), 7.18-7.28 (2H, m), 6.99 (1H, s), 6.88 (1H, m), 6.69 (1H, s), 4.49 (0.5H, t), 4.40 (0.5H, t), 4.00-4.25 (2H, m), 3.10-3.85 (5H, m), 1.45-2.10 (8H, m) ppm.
Preparation example 313,5-mesitylenic acid 3-(3, the 4-dichlorophenyl)-4-[2-(3, the 5-dimethylbenzoyl)
Imidazoles-1-yl] butyl
Ester
Figure A9880634200621
With 3,5-dimethyl benzoyl chloride (1.33g) is added drop-wise to 3-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-alcohol (0.75g) (referring to preparation example 19) and triethylamine (1.1g) in the suspension of anhydrous acetonitrile (15ml), with this solution stirring at room 120 hours.This mixture then with water (30ml) and methylene dichloride (50ml) mixture, separate organic phase, order water and salt water washing.Removal of solvent under reduced pressure; obtain a resistates; through silica gel chromatography; it with volume ratio 100: 0～99: 1 methylene dichloride: methyl alcohol gradient solvent wash-out; obtain yellow foamed 3; 5-mesitylenic acid 3-(3, the 4-dichlorophenyl)-4-[2-(3, the 5-dimethylbenzoyl) imidazoles-1-yl] butyl ester (0.94g). 1H-NMR(CDCl 3)：δ＝7.69(2H，s)，7.49(2H，s)，7.10-7.27(5H，m)，6.92(1H，dd)，6.81(1H，s)，4.76(1H，dd)，4.51(1H，dd)，4.10-4.30(2H，m)，3.32(1H，m)，2.35(6H，s)，2.29(6H，s)，2.19(2H，m)ppm.
Preparation example 32
2,3-dihydrobenzo [b] furans-7-formic acid
Figure A9880634200631
With N, N, N ', N '-Tetramethyl Ethylene Diamine (38ml) are dissolved in the hexane (300ml), cooling and adding n-Butyl Lithium (100ml 2.5M hexane solution) in ice bath.This mixture after 15 minutes, dripped 2,3-dihydrobenzo [b] furans (30g) with 30 minutes 0 ℃ of stirring.Make this mixture be warming to room temperature through 30 minutes, continue to stir 4 hours in room temperature, in the excessive solidified carbon dioxide of impouring, it was placed 3 days, this moment, solvent evaporated.Resistates is assigned between ethyl acetate (1L) and the 4N aqueous hydrochloric acid (240ml), separates each layer, water layer ethyl acetate extraction (500ml).Merge organic extract liquid, through anhydrous sodium sulfate drying and removal of solvent under reduced pressure.Resistates is developed with ether, obtains 2,3-dihydrobenzo [b] furans-7-formic acid (21g) white solid. 1H-NMR(CDCl 3)：δ＝7.75(1H，d)，7.31(1H，d)，6.88(1H，t)，4.69(2H，t)，3.20(2H，t)ppm.
Preparation example 33
1,2,3,4-tetrahydrochysene-5-naphthoic acid
Figure A9880634200632
Be added to 10%w/w palladium on carbon (10g) in the solution of 1-naphthoic acid (33.4g) in Glacial acetic acid (150ml) and make this mixture under 345kPa (50psi) in 85 ℃ of hydrogenations 4 days.Make this warm mixture filter flocculating aids Arbacel (trade(brand)name) short column, filter bed washs with Glacial acetic acid (150ml).Be added to water (1.5L) in the filtrate and leach the precipitation that obtains and wash with water.Precipitation is dissolved in the methylene dichloride, and solution obtains oily matter through anhydrous sodium sulfate drying and removal of solvent under reduced pressure, through the ethyl acetate crystallization, obtains 1,2,3,4-tetrahydrochysene-5-naphthoic acid (2.94g) white solid (fusing point: 148-150 ℃). 1H-NMR(CDCl 3)：δ＝7.85(1H，d)，7.28(1H，d)，7.16(1H，m)，3.15(2H，br.s)，2.84(2H，br.s)，1.72-1.90(4H，m)ppm.
Preparation example 34
1,2,3,4-tetrahydrochysene-6-naphthoic acid
Figure A9880634200641
With 1,2,3,4-tetrahydrochysene-6-naphthaldehyde (1.0g) is suspended in the 0.5M aqueous sodium hydroxide solution (125ml), and vigorous stirring also adds the 70%w/w tertbutyl peroxide aqueous solution (10.3ml).This mixture about 70 ℃ of heating 4 hours, was placed 3 days in room temperature then.Adding another part 70%w/w tertbutyl peroxide aqueous solution (10ml) also heats this mixture 24 hours at about 70 ℃.Make this mixture cooling, add ether (100ml) and separate each phase.Water is acidified to pH 1 and uses extracted with diethyl ether (2 * 100ml) with the 2N aqueous hydrochloric acid.Merge organic phase, through anhydrous sodium sulfate drying and removal of solvent under reduced pressure, obtain resistates, through silica gel chromatography, be 1: 1～1: 0 ether with volume ratio: pentane gradient solvent wash-out obtains 1,2,3 of white solid, 4-tetrahydrochysene-6-naphthoic acid (0.62g). 1H-NMR(CDCl 3)：δ＝7.78-7.86(2H，m)，7.14(1H，d)，2.78-2.87(4H，br.s)，1.79-1.88(4H，br.s)ppm.
Preparation example 35
2,3-dihydrobenzo [b] furans-7-formyl chloride
With 2,3-dihydrobenzo [b] furans-7-formic acid (3g) (referring to preparation example 32) is suspended in the anhydrous methylene chloride (30ml) and adds oxalyl chloride (3.5g), adds dimethyl formamide (3) then.Stirring at room 2.5 hours, removal of solvent under reduced pressure was dissolved in methylene dichloride and removal of solvent under reduced pressure with the gained resistates with this mixture.Resistates is dissolved in methylene dichloride once more, and removal of solvent under reduced pressure obtains 2 of pink solid shape once more, 3-dihydrobenzo [b] furans-7-formyl chloride (3.3g).
Preparation example 36
1,2,3,4-tetrahydrochysene-5-naphthoyl chloride
Figure A9880634200651
According to being similar to the method that embodiment 35 adopts, with 1,2,3,4-tetrahydrochysene-5-naphthoic acid (referring to preparation example 33) is as this compound of feedstock production.
Preparation example 37
1,2,3,4-tetrahydrochysene-6-naphthoyl chloride
Figure A9880634200652
According to being similar to the method that embodiment 35 adopts, with 1,2,3,4-tetrahydrochysene-6-naphthoic acid (referring to preparation example 34) is as this compound of feedstock production.
Preparation example 38～46
Employing is similar to the method for preparation example 31, the preparation example general formula compound of using 3-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-alcohol (referring to preparation example 19) and suitable acyl chlorides to list as feedstock production following table 2:
Figure A9880634200653
Table 2
Figure A9880634200671
Footnote: (a) the silica gel chromatography volume ratio is 1: 2～1: 0 a ethyl acetate: pentane gradient solvent wash-out.(b) silica gel chromatography ether wash-out.(c) the silica gel chromatography volume ratio is 1: 2～2: 1 a ethyl acetate: pentane gradient solvent wash-out.
Preparation example 473-(3, the 4-dichlorophenyl)-4-[2-(3, the 5-dimethylbenzoyl) imidazoles-1-yl] butane-1-
Alcohol
Figure A9880634200672
With 3,5-mesitylenic acid 3-(3, the 4-dichlorophenyl)-4-[2-(3, the 5-dimethylbenzoyl) imidazoles-1-yl] butyl ester (0.93g) (referring to preparation example 31) is dissolved in methyl alcohol (10ml), adds 2N aqueous sodium hydroxide solution (2ml).Form the heavy-gravity jelly, add other methyl alcohol (50ml), gained suspension is in stirred overnight at room temperature.Under reduced pressure remove methyl alcohol then, resistates is assigned between methylene dichloride (50ml) and the water (10ml).Separate organic phase; use the salt water washing; removal of solvent under reduced pressure; obtain crude product; through silica gel chromatography, with 99: 1～95: 5 methylene dichloride: methyl alcohol gradient solvent wash-out obtains 3-(3; the 4-dichlorophenyl)-and 4-[2-(3, the 5-dimethylbenzoyl) imidazoles-1-yl] butane-1-alcohol (0.67g) white foam. 1H-NMR(CDCl 3)：δ＝7.70(2H，s)，7.10-7.32(4H，m)，6.89(1H，d)，6.72(1H，s)，4.83(1H，dd)，4.40(1H，dd)，3.70-3.80(1H，m)，3.50-3.62(1H，m)，3.28-3.40(1H，m)，2.40(6H，s)，1.85-2.07(3H，m)，ppm.
Preparation example 48～53
Employing is similar to the method for preparation example 47, the general formula compound of the preparation example that raw material (referring to preparation example 38～41,44 and 46) the preparation following table 3 that usefulness is suitable is listed:
Figure A9880634200681
Table 3
Figure A9880634200691
Preparation example 54
3-(3, the 4-dichlorophenyl)-4-[2-(2-naphthoyl) imidazoles-1-yl] butane-1-alcohol
Figure A9880634200701
With 2-naphthoic acid 3-(3; the 4-dichlorophenyl)-and 4-[2-(2-naphthoyl) imidazoles-1-yl] butyl ester (1.25g) (referring to preparation example 42) is dissolved in 1; 4-diox (15ml), add 1N aqueous sodium hydroxide solution (4ml) and with this mixture in stirred overnight at room temperature.Remove diox under the decompression then, resistates is distributed between ethyl acetate and water.Separate organic phase; order 1N aqueous sodium hydroxide solution, water and salt water washing; removal of solvent under reduced pressure; obtain crude product; through silica gel chromatography; be 99: 1～95: 5 methylene dichloride with volume ratio: methyl alcohol gradient solvent wash-out obtains gluey 3-(3, the 4-dichlorophenyl)-4-[2-(2-naphthoyl) imidazoles-1-yl] butane-1-alcohol (0.8g). 1H-NMR(CDCl 3)：δ＝8.82(1H，s)，8.16(1H，d)，7.99(1H，d)，7.89(2H，t)，7.50-7.63(2H，m)，7.26(1H，d)，7.16(1H，d)，6.90(1H，dd)，6.76(1H，s)，4.90(1H，dd)，4.43(1H，dd)，3.69-3.83(1H，m)，3.51-3.68(1H，m)，3.32-3.45(1H，m)，1.86-2.08(3H，m)ppm.
Preparation example 55～56
Employing is similar to the method for preparation example 54, the general formula compound of the preparation example that raw material (referring to preparation example 43 and 45) the preparation following table 4 that usefulness is suitable is listed:
Figure A9880634200702
Table 4 Footnote: (a) the silica gel chromatography volume ratio is 1: 0～0: 1 a ether: ethyl acetate gradient solvent wash-out.
Preparation example 57
1-[2-(2-anisoyl) imidazoles-1-yl]-2-(3, the 4-dichlorophenyl)
-4-(tetrahydropyrans-2-base oxygen base) butane
Figure A9880634200712
Under nitrogen atmosphere, with 1-(imidazoles-1-yl)-2-(3, the 4-dichlorophenyl)-and 4-(tetrahydropyrans-2-base oxygen base) butane (0.86g) (referring to preparation example 30) and triethylamine (1.3ml) be dissolved in acetonitrile (15ml), and this solution is cooled off in ice bath and drip 2-methoxy benzoyl chloride (1.4ml).Make this mixture be warming to room temperature lentamente, stirred then 2 days.Remove acetonitrile under the decompression, resistates is dissolved in methylene dichloride (20ml) and order water and salt water washing.Organic phase is through anhydrous sodium sulfate drying and removal of solvent under reduced pressure; obtain a resistates; through silica gel chromatography; it with volume ratio 97: 3 methylene dichloride: methanol-eluted fractions; obtain 1-[2-(2-anisoyl) imidazoles-1-yl of buttery non-enantiomer mixture form]-2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butane (1.1g). 1H-NMR (CDCl 3) (mixtures of 2 diastereomers): δ=6.76-7.52 (9H, m), 4.10-4.90 (3H, m), 3.11-3.90 (8H, m), 1.45-2.25 (6H, m), 1.26 (1H, t), 1.06 (1H, t) ppm.
Preparation example 58～62
Employing is similar to the method for preparation example 57, the general formula compound of the preparation example that the feedstock production following table 5 that usefulness is suitable is listed:
Figure A9880634200721
Table 5
Preparation example 63
1-ethoxyl methyl imidazoles
Under nitrogen atmosphere, imidazoles (20g) is dissolved in tetrahydrofuran (THF) (700ml), be cooled to-70 ℃ also with 15 minutes dropping n-Butyl Lithiums (117.5ml 2.5M hexane solution).Make this mixture be warming to-20 ℃ and stirred 30 minutes, drip chloromethyl ethyl ether (30.5g) afterwards at-20 ℃.Make this mixture be warming to room temperature and restir 1 hour.Removal of solvent under reduced pressure obtains resistates, develops and filter the filter bed of a short flocculating aids Arbacel (trade(brand)name) with methylene dichloride.Filtrate decompression is removed and is desolvated, and obtains a mobile oil, through underpressure distillation (0.7 millibar, 0.53mm Hg), obtains oily 1-ethoxyl methyl imidazoles (20.8g). 1H-NMR(CDCl 3)：δ＝7.61(1H，s)，7.09(2H，d)，5.29(2H，s)，3.49(2H，q)，1.21(3H，t)ppm.
Preparation example 64
1-ethoxyl methyl-2-phenylacetyl imidazoles
Figure A9880634200741
Under nitrogen atmosphere, 1-ethoxyl methyl imidazoles (11.98g) (referring to preparation example 63) is dissolved in tetrahydrofuran (THF) (400ml), be cooled to-70 ℃, with 5 minutes dropping n-Butyl Lithiums (40ml 2.5M hexane solution).This mixture was stirred 1 hour at-70 ℃, drip chlorine trimethyl silane (10.83g).Make after stirring 1 hour it be warming to room temperature and restir 3 hours at-70 ℃ in this mixture.Add phenyllacetyl chloride (14.68g) and continue and stirred 18 hours, afterwards removal of solvent under reduced pressure.The gained resistates is dissolved in methylene dichloride, and order water, saturated sodium bicarbonate aqueous solution and salt water washing are through anhydrous sodium sulfate drying.Decompression removes from organic phase and desolvates.Crude product is 95: 5 methylene dichloride through silica gel chromatography with volume ratio: methanol-eluted fractions obtains oily 1-ethoxyl methyl-2-phenylacetyl imidazoles (8.23g). 1H-NMR(CDCl 3)：δ＝7.19-7.39(7H，m)，5.72(2H，s)，4.43(2H，s)，3.48(2H，q)，1.14(3H，t)ppm.
Embodiment 65
2-phenylacetyl imidazoles
1-ethoxyl methyl-2-phenylacetyl imidazoles (8.23g) (referring to preparation example 64) was dissolved in ethanol (200ml), adds 2N aqueous hydrochloric acid (200ml), with gained suspension reflux 30 minutes.The ethanol (50ml) that adds another part to dissolve remaining suspended substance, makes it place in room temperature this mixture reheat backflow and spends the night after 6 hours.Organic solvent is removed in decompression, and the adding saturated sodium bicarbonate aqueous solution alkalizes to pH9 in the gained aq suspension.Then with dichloromethane extraction three times of this mixture.Merge organic extract liquid,, obtain 2-phenylacetyl imidazoles (6.29g) yellow solid through anhydrous sodium sulfate drying and removal of solvent under reduced pressure. 1H-NMR(CDCl 3)：δ＝7.19-7.39(7H，m)，4.40(2H，s)ppm.
Preparation example 661-[2-phenylacetyl imidazoles-1-yl]-2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen
Base) butane
1-mesyloxy-2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butane (0.57g) (referring to preparation example 29) and 2-phenylacetyl imidazoles (0.27g) (referring to preparation example 65) are dissolved in acetonitrile (20ml).Add salt of wormwood (0.41g) and reflux 18 hours under nitrogen atmosphere.Cool off this mixture, removal of solvent under reduced pressure, resistates is assigned between methylene dichloride and the water.Separate organic phase, use the salt water washing, through anhydrous sodium sulfate drying and removal of solvent under reduced pressure.The gained resistates is through silica gel chromatography; it with volume ratio 99: 1 methylene dichloride: methanol-eluted fractions; obtain the 1-[2-phenylacetyl imidazoles-1-yl of buttery non-enantiomer mixture form]-2-(3, the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butane (0.23g). 1H-NMR (CDCl 3) (mixtures of 2 diastereomers): δ=7.22-7.38 (6H, m), 7.05-7.12 (2H, m), 6.71-6.84 (2H, m), 4.64-4.76 (1H, m), 4.28-4.50 (4H, m), 3.10-3.79 (5H, m), 1.42-2.05 (8H, m) ppm.
Preparation example 673-(3, the 4-dichlorophenyl)-4-[2-(2-anisoyl) imidazoles-1-yl] butane-1-alcohol
Figure A9880634200761
With 1-[2-(2-anisoyl) imidazoles-1-yl]-2-(3; the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butane (1.1g) (referring to preparation example 57) is dissolved in methyl alcohol (20ml), add Amberlyst 15 (trade(brand)name) ion exchange resin (0.11g) and with this mixture stirring at room 5 days.Filter flocculating aids Arbacel (trade(brand)name) short column and remove resin, filtrate decompression is removed and is desolvated, and obtains a resistates.Through silica gel chromatography, be 97: 3 methylene dichloride with volume ratio: methanol-eluted fractions obtains 3-(3, the 4-dichlorophenyl)-4-[2-(2-anisoyl)-imidazoles-1-yl] butane-1-alcohol (0.31g) white foam. 1H-NMR(CDCl 3)：δ＝7.19-7.48(4H，m)，6.91-7.06(4H，m)，6.67(1H，s)，4.93(1H，dd)，4.36(1H，dd)，3.52-3.80(2H，m)，3.80(3H，s)，3.30-3.41(1H，m)，1.90-2.03(2H，m)，1.72(1H，br.s)ppm.
Preparation example 68
3-(3, the 4-dichlorophenyl)-4-[2-(3,5-two (trifluoromethyl) benzoyl)
Imidazoles-1-yl] butane-1-alcohol
According to the method that is similar to preparation example 67, the compound of using preparation example 58 is as feedstock production 3-(3, the 4-dichlorophenyl)-4-[2-(3,5-two (trifluoromethyl) benzoyl) imidazoles-1-yl] butane-1-alcohol. 1H-NMR(CDCl 3)：δ＝8.76(2H，s)，8.08(1H，s)，7.30(1H，d)，7.19(2H，d)，6.85-6.92(2H，m)，4.88(1H，dd)，4.50(1H，dd)，3.71-3.81(1H，m)，3.51-3.63(1H，m)，3.30-3.42(1H，m)，1.90-2.10(2H，m)，1.71(1H，t)ppm.
Preparation example 69
3-(3, the 4-dichlorophenyl)-4-[2-(2-trifluoromethyl benzoyl)
Imidazoles-1-yl] butane-1-alcohol
Figure A9880634200772
With 1-[2-(2-trifluoromethyl benzoyl) imidazoles-1-yl]-2-(3; the 4-dichlorophenyl)-4-(tetrahydropyrans-2-base oxygen base) butane (0.68g) (referring to preparation example 59) is dissolved in methyl alcohol (15ml); this methyl alcohol is to use hydrogen chloride gas saturated in advance, and this mixture was placed 4 hours.Removal of solvent under reduced pressure obtains resistates then, and it is distributed in (water layer pH remains on 8-9) between methylene dichloride and the saturated sodium bicarbonate aqueous solution.Separate organic phase, twice of dichloromethane extraction of water.Merge organic phase then,, obtain white foam shape 3-(3, the 4-dichlorophenyl)-4-[2-(2-trifluoromethyl benzoyl) imidazoles-1-yl through anhydrous sodium sulfate drying and removal of solvent under reduced pressure] butane-1-alcohol (0.41g). 1H-NMR(CDCl 3)：δ＝7.77(1H，d)，7.54-7.69(2H，m)，7.47(1H，m)，7.32(1H，d)，7.22(1H，d)，7.07(1H，s)，6.91(1H，dd)，6.74(1H，s)，4.98(1H，dd)，4.42(1H，dd)，3.70-3.81(1H，m)，3.52-3.67(1H，m)，3.28-3.41(1H，m)，1.90-2.09(2H，m)，1.77(1H，br.s)ppm.
Preparation example 70～73
Employing is similar to the method for preparation example 69, the general formula compound of the preparation example that raw material (referring to preparation example 60～62 and 66) the preparation following table 6 of using suitable THP trtrahydropyranyl to protect is listed:
Figure A9880634200781
Table 6 Footnote: (a) product is purified by silica gel chromatography, is 98: 2 methylene dichloride with volume ratio: methanol-eluted fractions.
Preparation example 74
1-mesyloxy-3-(3, the 4-dichlorophenyl)-4-[2-(3, the 5-dimethylbenzoyl)
Imidazoles-1-yl] butane
Figure A9880634200791
With 3-(3; the 4-dichlorophenyl)-4-[2-(3; the 5-dimethylbenzoyl) imidazoles-1-yl] butane-1-alcohol (0.63g) (referring to preparation example 47) and triethylamine (0.20g) be dissolved in methylene dichloride (12ml), cooling and add methylsulfonyl chloride (0.19g) in ice bath.This mixture was stirred 30 minutes, adds methylene dichloride (35ml), this solution order water (2 * 30ml) and salt solution (30ml) wash.Organic phase is through anhydrous sodium sulfate drying and removal of solvent under reduced pressure.Resistates is dissolved in acetonitrile, and removal of solvent under reduced pressure obtains oily 1-mesyloxy-3-(3, the 4-dichlorophenyl)-4-[2-(3, the 5-dimethylbenzoyl) imidazoles-1-yl]-butane (0.72g). 1H-NMR(CDCl 3)：δ＝7.68(2H，s)，7.10-7.32(4H，m)，6.91(1H，dd)，6.83(1H，s)，4.73(1H，dd)，4.53(1H，dd)，4.15-4.24(1H，m)，4.00-4.10(1H，m)，3.26-3.36(1H，m)，2.92(3H，s)，2.40(6H，s)，2.05-2.28(2H，m)ppm.
Preparation example 75～90
Employing is similar to the method for preparation example 74, the general formula compound of the preparation example that raw polyol (referring to preparation example 48～56 and 67～73) the preparation following table 7 that usefulness is suitable is listed:
Figure A9880634200792
Table 7
Figure A9880634200801
Figure A9880634200821
Preparation example 914 (S)-(3, the 4-dichlorophenyl)-5-hydroxyl penta-1-alkene
Figure A9880634200822
With 4 (S)-benzyl-3-(2 (S)-(3; the 4-dichlorophenyl) penta-4-alkene-1-acyl group) oxazolidine-2-ketone (30.32g) is (referring to biological organic and pharmaceutical chemistry communication (Bioorganic andMedicinal Chemistry Letters); 3; 319; (1993)) be dissolved in anhydrous tetrahydro furan (400ml), cooling also adds lithium aluminum hydride (5.7g) (thermopositive reaction) at twice carefully in ice bath.This mixture was stirred 20 minutes at 0 ℃, stirring at room 1 hour, be cooled to 0 ℃ afterwards then.After adding entry (6ml) carefully, add 2N aqueous sodium hydroxide solution (6ml), add entry (12ml) afterwards again.With this mixture vigorous stirring 40 minutes, the gained precipitation was by removing by filter, and washed with ether.Collect filtrate, separate organic phase and water.The organic phase removal of solvent under reduced pressure obtains yellow oil, and through silica gel chromatography, be 4: 1～4: 0 methylene dichloride with volume ratio: the hexane gradient solvent elution obtains oily 4 (S)-(3, the 4-dichlorophenyl)-5-hydroxyl penta-1-alkene (11.74g). 1H-NMR(CDCl 3)：δ＝7.24-7.45(2H，m)，7.06(1H，dd)，5.61-5.75(1H，m)，4.96-5.10(2H，m)，3.70-3.90(2H，m)，2.80-2.91(1H，m)，2.30-2.55(2H，m)，1.32(1H，t)ppm.
Preparation example 92
4 (R)-(3, the 4-dichlorophenyl)-5-hydroxyl penta-1-alkene
Figure A9880634200831
Employing is similar to the method for preparation example 91, this compound of feedstock production that usefulness is suitable (referring to: biological organic and pharmaceutical chemistry communication, 3,319, (1993)). 1H-NMR(CDCl 3)：δ＝7.24-7.45(2H，m)，7.06(1H，dd)，5.61-5.75(1H，m)，4.96-5.10(2H，m)，3.70-3.90(2H，m)，2.80-2.91(1H，m)，2.30-2.55(2H，m)，1.32(1H，t)ppm.
Preparation example 93
4 (S)-(3, the 4-dichlorophenyl)-5-(mesyloxy) penta-1-alkene
Figure A9880634200841
Methylsulfonyl chloride (3.55g) is added drop-wise in methylene dichloride (100ml) solution of 4 ice-cooled (S)-(3, the 4-dichlorophenyl)-5-hydroxyl penta-1-alkene (6.0g) (referring to preparation example 91) and triethylamine (3.48g), with this mixture stirring at room 1 hour.Removal of solvent under reduced pressure, resistates are assigned between ether and the water.Separate two-phase, water is further used extracted with diethyl ether.Merge organic phase and order water, rare aqueous citric acid solution, salt solution, saturated sodium bicarbonate aqueous solution and salt water washing, through anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains oily 4 (S)-(3, the 4-dichlorophenyl)-5-(mesyloxy) penta-1-alkene (8.25g). 1H-NMR(CDCl 3)：δ＝7.42(1H，d)，7.30(1H，s)，7.04(1H，dd)，5.56-5.72(1H，m)，5.01-5.10(2H，m)，4.22-4.39(2H，m)，3.05-3.15(1H，m)，2.88(3H，s)，2.33-2.60(2H，m)ppm.
Preparation example 94
4 (R)-(3, the 4-dichlorophenyl)-5-(mesyloxy) penta-1-alkene
Figure A9880634200842
Employing is similar to the method for preparation example 93, with 4 (R)-(3, the 4-dichlorophenyl)-5-hydroxyl penta-1-alkene (referring to preparation example 92) as this compound of feedstock production. 1H-NMR(CDCl 3)：δ＝7.42(1H，d)，7.30(1H，s)，7.04(1H，dd)，5.56-5.72(1H，m)，5.01-5.10(2H，m)，4.22-4.39(2H，m)，3.05-3.15(1H，m)，2.88(3H，s)，2.33-2.60(2H，m)ppm.
Preparation example 95
4 (S)-(3, the 4-dichlorophenyl)-5-(imidazoles-1-yl) penta-1-alkene
4 (S)-(3, the 4-dichlorophenyl)-5-(mesyloxy) penta-1-alkene (8.25g) (referring to preparation example 93) and imidazoles (5.3g) are dissolved in the anhydrous acetonitrile (80ml) also with this mixture heating up backflow 6 days.Removal of solvent under reduced pressure obtains resistates, it is assigned between ether and the saturated sodium bicarbonate aqueous solution (water pH remain on＞7).Separate each phase, the water extracted with diethyl ether, merge organic extract liquid, wash with water,, obtain resistates through anhydrous sodium sulfate drying and removal of solvent under reduced pressure, through silica gel chromatography, be 98: 2～95: 5 methylene dichloride with volume ratio: methyl alcohol gradient solvent wash-out obtains oily 4 (S)-(3, the 4-dichlorophenyl)-5-(imidazoles-1-yl) penta-1-alkene (4.78g). 1H-NMR(CDCl 3)：δ＝7.35(1H，d)，7.15-7.30(2H，m)，6.99(1H，s)，6.84(1H，d)，6.69(1H，s)，5.55-5.70(1H，m)，5.07(2H，d)，3.95-4.22(2H，m)，2.95-3.10(1H，m)，2.32-2.45(2H，m)ppm.
Preparation example 96
4 (R)-(3, the 4-dichlorophenyl)-5-(imidazoles-1-yl) penta-1-alkene
Figure A9880634200852
Employing is similar to the method for preparation example 95, with 4 (R)-(3, the 4-dichlorophenyl)-5-(mesyloxy) penta-1-alkene (referring to preparation example 94) as this compound of feedstock production. 1H-NMR(CDCl 3)：δ＝7.35(1H，d)，7.15-7.30(2H，m)，6.99(1H，s)，6.84(1H，d)，6.69(1H，s)，5.55-5.70(1H，m)，5.07(2H，d)，3.95-4.22(2H，m)，2.95-3.10(1H，m)，2.32-2.45(2H，m)ppm.
Preparation example 97
3 (S)-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-aldehyde
4 (S)-(3, the 4-dichlorophenyl)-5-(imidazoles-1-yl) penta-1-alkene (4.75g) (referring to preparation example 95) is dissolved in the mixed solution of acetonitrile (75ml), water (13ml) and 1N aqueous hydrochloric acid (17ml).Adding perosmic anhydride (3.4ml 0.05M toluene solution) also stirs this mixture 20 minutes.Adding sodium periodate (5.3g) and another part acetonitrile (30ml) then also continues to stir to spend the night.Add entry (about 100ml), acetonitrile is removed in decompression, obtains aq suspension, adds solid sodium carbonate and alkalizes to pH＞7.Ethyl acetate extraction three times of this mixture, the organic extract liquid order water and the salt water washing of merging are through anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains oily 3 (S)-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-aldehyde (4.3g). 1H-NMR(CDCl 3)：δ＝9.70(1H，s)，7.38(1H，d)，7.20-7.30(2H，m)，7.01(1H，s)，6.89(1H，dd)，6.71(1H，s)，4.00-4.22(2H，m)，3.60(1H，m)，2.72-2.92(2H，m)ppm.
Preparation example 98
3 (R)-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-aldehyde
Figure A9880634200862
Employing is similar to the method for preparation example 97, with 4 (R)-(3, the 4-dichlorophenyl)-5-(imidazoles-1-yl) penta-1-alkene (referring to preparation example 96) as this compound of feedstock production. 1H-NMR(CDCl 3)：δ＝9.70(1H，s)，7.38(1H，d)，7.20-7.30(2H，m)，7.01(1H，s)，6.89(1H，dd)，6.71(1H，s)，4.00-4.22(2H，m)，3.60(1H，m)，2.72-2.92(2H，m)ppm.
Preparation example 99
3 (S)-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-alcohol
Carefully sodium borohydride (0.68g) is added to 3 ice-cooled (S)-(3, the 4-dichlorophenyl)-ethanol (40ml) solution of 4-(imidazoles-1-yl) butane-1-aldehyde (4.3g) (referring to preparation example 97) in, in stirring at room after 1 hour, removal of solvent under reduced pressure obtains resistates with this mixture.This resistates is suspended in the water (30ml), cools off in ice bath, this mixture at first is acidified to pH1 with the 2N aqueous hydrochloric acid, adds the 2N aqueous sodium hydroxide solution then and alkalizes to pH14.With the gained suspension filtered, resistates washes with water, and drying is used the acetonitrile crystallization then, obtains emulsus solid 3 (S)-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-alcohol (1.37g). 1H-NMR(CDCl 3)：δ＝7.35(1H，d)，7.15-7.30(2H，m)，6.95(1H，s)，6.89(1H，d)，6.70(1H，s)，4.00-4.25(2H，m)，3.60-3.70(1H，m)，3.40-3.50(1H，m)，3.15-3.30(1H，m)，2.10(1H，br.s)，1.75-2.00(2H，m)ppm.
Preparation example 100
3 (R)-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-alcohol
Employing is similar to the method for preparation example 99, with 3 (R)-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-aldehyde (referring to preparation example 98) as this compound of feedstock production. 1H-NMR(CDCl 3)：δ＝7.35(1H，d)，7.15-7.30(2H，m)，6.95(1H，s)，6.89(1H，d)，6.70(1H，s)，4.00-4.25(2H，m)，3.60-3.70(1H，m)，3.40-3.50(1H，m)，3.15-3.30(1H，m)，2.10(1H，br.s)，1.75-2.00(2H，m)ppm.
Preparation example 1011,2,3, and 4-tetrahydrochysene-5-naphthoic acid 3 (S)-(3, the 4-dichlorophenyl)-4-[2-(1,2,3, the 4-tetrahydrochysene
-5-naphthoyl) imidazoles-1-yl] butyl] ester
Figure A9880634200881
With 1,2,3,4-tetrahydrochysene-5-naphthoyl chloride (1.70g) (referring to preparation example 36) is added drop-wise to 3 (S)-(3, the 4-dichlorophenyl)-anhydrous acetonitrile (15ml) solution of 4-(imidazoles-1-yl) butane-1-alcohol (0.90g) (referring to preparation example 99) and triethylamine (1.45g) in, with this solution stirring at room 4 days.Removal of solvent under reduced pressure obtains a resistates, and it is assigned between ethyl acetate and the saturated sodium bicarbonate aqueous solution.Separate each phase, water is further used ethyl acetate extraction.Merge organic phase, order water and salt water washing are through anhydrous sodium sulfate drying; removal of solvent under reduced pressure obtains resistates, through silica gel chromatography; be 2: 1～0: 1 pentane with volume ratio: ethyl acetate gradient solvent wash-out obtains gluey 1,2; 3; 4-tetrahydrochysene-5-naphthoic acid 3 (S)-(3, the 4-dichlorophenyl)-4-[2-(1,2; 3,4-tetrahydrochysene-5-naphthoyl) imidazoles-1-yl] butyl ester (1.38g). 1H-NMR(CDCl 3)：δ＝7.50(1H，d)，6.95-7.38(10H，m)，4.83(1H，dd)，4.63(1H，m)4.30-4.35(1H，m)，4.08-4.16(1H，m)，3.30-3.40(1H，m)，3.00(2H，br.s)，2.63-2.84(6H，m)，2.10-2.25(2H，m)，1.67-1.83(8H，m)ppm.
Preparation example 1021,2,3, and 4-tetrahydrochysene-5-naphthoic acid 3 (R)-(3, the 4-dichlorophenyl)-4-[2-(1,2,3, the 4-tetrahydrochysene
-5-naphthoyl) imidazoles-1-yl] butyl ester
Employing is similar to the method for preparation example 101, with 3 (R)-(3, the 4-dichlorophenyl)-4-(imidazoles-1-yl) butane-1-alcohol (referring to preparation example 100) as this compound of feedstock production. 1H-NMR(CDCl 3)：δ＝7.50(1H，d)，6.95-7.38(10H，m)，4.83(1H，dd)，4.63(1H，m)，4.30-4.35(1H，m)，4.08-4.16(1H，m)，3.30-3.40(1H，m)，3.00(2H，br.s)，2.63-2.84(6H，m)，2.10-2.25(2H，m)，1.67-1.83(8H，m)ppm.
Preparation example 103
3 (S)-(3, the 4-dichlorophenyl)-4-[2-(1,2,3,4-tetrahydrochysene-5-naphthoyl)
Imidazoles-1-yl] butane-1-alcohol
Figure A9880634200891
With 1; 2; 3; 4-tetrahydrochysene-5-naphthoic acid 3 (S)-(3; the 4-dichlorophenyl)-4-[2-(1,2,3; 4-tetrahydrochysene-5-naphthoyl) imidazoles-1-yl] butyl ester (1.38g) (referring to preparation example 101) is dissolved in methyl alcohol (40ml), add 1N aqueous sodium hydroxide solution (5ml) and with the gained mixture in stirred overnight at room temperature.Methyl alcohol is removed in decompression, and resistates is assigned between ethyl acetate and the water.Separate organic phase, order is with saturated sodium bicarbonate aqueous solution and salt water washing, through anhydrous sodium sulfate drying and removal of solvent under reduced pressure; obtain gluey 3 (S)-(3, the 4-dichlorophenyl)-4-[2-(1,2; 3,4-tetrahydrochysene-5-naphthoyl) imidazoles-1-yl] butane-1-alcohol (0.82g). 1H-NMR(CDCl 3)：δ＝7.10-7.35(5H，m)，7.06(1H，s)，6.92(1H，dd)，6.74(1H，s)，4.90(1H，dd)，4.50(1H，dd)，3.70-3.82(1H，m)，3.53-3.64(1H，m)，3.30-3.42(1H，m)，2.70-2.86(4H，m)，1.70-2.04(6H，m)ppm.
Preparation example 104
3 (R)-(3, the 4-dichlorophenyl)-4-[2-(1,2,3,4-tetrahydrochysene-5-naphthoyl) imidazoles-1-yl] butane-1-alcohol
Figure A9880634200901
Employing is similar to the method for preparation example 103, with 1,2,3,4-tetrahydrochysene-5-naphthoic acid 3 (R)-(3, the 4-dichlorophenyl)-4-[2-(1,2,3,4-tetrahydrochysene-5-naphthoyl) imidazoles-1-yl] butyl ester (referring to preparation example 102) is as this compound of feedstock production. 1H-NMR(CDCl 3)：δ＝7.10-7.35(5H，m)，7.06(1H，s)，6.92(1H，dd)，6.74(1H，s)，4.90(1H，dd)，4.50(1H，dd)，3.70-3.82(1H，m)，3.53-3.64(1H，m)，3.30-3.42(1H，m)，2.70-2.86(4H，m)，1.70-2.04(6H，m)ppm.
Preparation example 1051-mesyloxy-3 (S)-(3, the 4-dichlorophenyl)-4-[2-(1,2,3,4-tetrahydrochysene-5-naphthalene first
Acyl group) imidazoles-1-yl] butane
Figure A9880634200902
With 3 (S)-(3; the 4-dichlorophenyl)-4-[2-(1,2,3; 4-tetrahydrochysene-5-naphthoyl) imidazoles-1-yl] butane-1-alcohol (0.68g) (referring to preparation example 103) and triethylamine (0.22g) be dissolved in methylene dichloride (15ml), and this solution is cooled off in ice bath and add methylsulfonyl chloride (0.22g).After 4 hours, removal of solvent under reduced pressure obtains a resistates, and it is allocated between ethyl acetate and the water with this mixture stirring.Separate organic phase, after the saturated sodium bicarbonate aqueous solution washing, through anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains oily 1-mesyloxy-3 (S)-(3, the 4-dichlorophenyl)-4-[2-(1,2,3,4-tetrahydrochysene-5-naphthoyl) imidazoles-1-yl] butane (0.82g). 1H-NMR(CDCl 3)：δ＝7.37(1H，d)，7.05-7.31(5H，m)，6.99(1H，dd)，6.84(1H，s)，4.80(1H，dd)，4.65(1H，dd)，4.05-4.30(2H，m)，3.30-3.40(1H，m)，2.97(3H，s)，2.65-2.85(4H，m)，2.10-2.30(2H，m)，1.70-1.85(4H，m)ppm.
Preparation example 106 1-mesyloxies-3 (R)-(3, the 4-dichlorophenyl)-4-[2-(1,2,3,4-tetrahydrochysene-5-naphthalene first
Acyl group) imidazoles-1-yl] butane
Employing is similar to the method for preparation example 105, with 3 (R)-(3, the 4-dichlorophenyl)-4-[2-(1,2,3,4-tetrahydrochysene-5-naphthoyl) imidazoles-1-yl] butane-1-alcohol (referring to preparation example 104) is as this compound of feedstock production. 1H-NMR(CDCl 3)：δ＝7.37(1H，d)，7.05-7.31(5H，m)，6.99(1H，dd)，6.84(1H，s)，4.80(1H，dd)，4.65(1H，dd)，4.05-4.30(2H，m)，3.30-3.40(1H，m)，2.97(3H，s)，2.65-2.85(4H，m)，2.10-2.30(2H，m)，1.70-1.85(4H，m)ppm.
Pharmacology data
Adopt the method for the 24th page of the 8th～22 line description of this specification sheets to measure the following example compound to people NK 1And NK 2The affinity of acceptor, following table has been represented the result.
Embodiment number ????NK 1In conjunction with (IC 50) ????NK 2In conjunction with (IC 50)
Embodiment 2 ????0.6nM ????4nM
Embodiment 5 ????8nM ????11nM
Embodiment 6 ????9nM ????96nM
Embodiment 18 ????123nM ????3nM
Embodiment 19 ????2nM ????24nM
These data show that described compound is NK 1And NK 2The dual antagonist of acceptor.

Claims (33)

1, a kind of formula (I) compound:
Figure A9880634200021
Wherein R is a phenyl, C 3-C 7Cycloalkyl or heteroaryl, described group can at random be benzo-or C 3-C 7Cycloalkylfused, and can at random be replaced by 1～3 substituting group, be included in benzo-or C 3-C 7Be substituted in the Cycloalkylfused part, described substituting group is independently from each other C 1-C 4Alkyl, fluoro (C 1-C 4) alkyl, C 1-C 4Alkoxyl group, fluoro (C 1-C 4) alkoxyl group, phenoxy group, C 2-C 4Alkanoyl, halogen, C 1-C 4Alkoxy carbonyl, C 3-C 7Cycloalkyl ,-S (O) m(C 1-C 4) alkyl, cyano group ,-NR 2R 3,-S (O) mNR 2R 3,-NR 4(C 1-C 4Alkanoyl) and-CONR 2R 3, perhaps R is 2,3-dihydrobenzo [b] furyl or chromanyl; R 1Be H or C 1-C 6Alkyl; R 2And R 3Be independently from each other H and C 1-C 6Alkyl, perhaps the two represents C together 4-C 6Alkylidene group; R 4Be H or C 1-C 6Alkyl; W is direct key, methylene radical or ethylidene; X is a straight chain C 2-C 4Alkylidene group; Y is phenyl, naphthyl, benzyl, pyridyl, thienyl or C 3-C 7Cycloalkyl, they can at random be independently from each other following substituting group by 1～3 separately and replace: C 1-C 4Alkyl, fluoro (C 1-C 4) alkyl, C 1-C 4Alkoxyl group, fluoro (C 1-C 4) alkoxyl group, halogen and cyano group; Ar is phenyl, naphthyl, benzyl, thienyl, benzo [b] thienyl or indyl, and they can at random be independently from each other following substituting group by 1～3 separately and replace: C 1-C 4Alkyl, fluoro (C 1-C 4) alkyl, C 1-C 4Alkoxyl group, fluoro (C 1-C 4) alkoxyl group, halogen and cyano group, perhaps Ar is 1,3-benzo dioxolane-4-or-5-base or 1,4-benzodioxan-5-or-the 6-base; M is 0,1 or 2; Z AIt is pharmaceutically acceptable negatively charged ion; " heteroaryl " that uses in the R definition is meant thienyl or contains 1～4 nitrogen heteroatom or 5 or 6 yuan of ring heteroaryls of 1 or 2 nitrogen heteroatom and 1 oxygen or sulfur heteroatom, condition be when W be direct key and R when being any condensed and any substituted heteroaryl, described heteroaryl links to each other with carbonyl by ring carbon atom.
2, the compound of claim 1, wherein R is a phenyl, it can at random be benzo-or C 3-C 7Cycloalkylfused, and can at random be replaced by 1,2 or 3 substituting group, be included in benzo-or C 3-C 7Replace in the Cycloalkylfused part, described substituting group is independently from each other C 1-C 4Alkyl, fluoro (C 1-C 4) alkyl, C 1-C 4Alkoxyl group, fluoro (C 1-C 4) alkoxyl group, phenoxy group and halogen or R be 2,3-dihydrobenzo [b] furyl.
3, claim 1 or 2 compound, wherein R is a phenyl, it can at random be benzo-or C 3-C 7Cycloalkylfused, and can at random be replaced by 1,2 or 3 substituting group, be included in benzo-or C 3-C 7Replace in the Cycloalkylfused part, described substituting group is independently from each other methyl, ethyl, trifluoromethyl, methoxyl group, isopropoxy, trifluoromethoxy, phenoxy group, fluorine and chlorine, and perhaps R is 2,3-dihydrobenzo [b] furyl.
4, claim 1,2 or 3 compound, wherein R is phenyl, naphthyl or tetralyl, they can at random be independently selected from following substituting group by 1,2 or 3 separately and replace: methyl, ethyl, trifluoromethyl, methoxyl group, isopropoxy, trifluoromethoxy, phenoxy group, fluorine and chlorine, perhaps R is 2,3-dihydrobenzo [b] furyl.
5, each compound of claim 1-4, wherein R is a phenyl, 3,5-3,5-dimethylphenyl, 2,3-3,5-dimethylphenyl, 2-Trifluoromethoxyphen-l, 2-methoxyl group-3-aminomethyl phenyl, 2,3-dihydrobenzo [b] furans-7-base, naphthalene-2-base, 4-fluoro-3-trifluoromethyl, 1,2,3,4-naphthane-5-base, 1,2,3,4-naphthane-6-base, 5-chloro-2-p-methoxy-phenyl, 2-p-methoxy-phenyl, 2-trifluoromethyl, 2-isopropyl phenyl, 2-ethylphenyl, 2-Phenoxyphenyl or 3,5-two (trifluoromethyl) phenyl.
6, each compound of claim 1-5, wherein R is 2,3-3,5-dimethylphenyl, naphthalene-2-base, 1,2,3,4-naphthane-5-base or 2-p-methoxy-phenyl.
7, each compound of claim 1-6, wherein R 1Be H.
8, each compound of claim 1-7, wherein W is a direct key or a methylene radical.
9, each compound of claim 1-8, wherein W is a direct key.
10, each compound of claim 1-9, wherein X is an ethylene.
11, each compound of claim 1-10, wherein Y is phenyl, naphthyl or cyclohexyl, they separately can be at random by 1,2 or 3 C 1-C 4Alkyl substituent replaces.
12, each compound of claim 1-11, wherein Y is a phenyl, 3,5-dimethyl base phenyl, cyclohexyl or naphthalene-2-base.
13, each compound of claim 1-12, wherein Y is a phenyl.
14, each compound of claim 1-13, wherein Ar is the phenyl that can at random be replaced by 1,2 or 3 halogenic substituent.
15, each compound of claim 1-14, the wherein phenyl that replaced by 1 or 2 chlorine substituent of Ar.
16, each compound of claim 1-15, wherein Ar is 3, the 4-dichlorophenyl.
17, each compound of claim 1-16, wherein Z ABe chlorion, bromide anion, nitrate radical, methanesulfonate, tosic acid root, Phenylsulfonic acid root, bisulfate ion or sulfate radical.
18, each compound of claim 1-17, wherein Z ABe chlorion or methanesulfonate.
19, each compound of claim 1-18, wherein Z AIt is methanesulfonate.
20, the compound of claim 1, wherein R 1Be H, X is-CH 2CH 2-and Ar be 3,4-dichlorophenyl, and wherein R-W-is 3,5-3,5-dimethylphenyl, Y are phenyl and Z ABe CH 3SO 3 -R-W-is 2, and 3-3,5-dimethylphenyl, Y are phenyl and Z ABe CH 3SO 3 -R-W-is the 2-Trifluoromethoxyphen-l, and Y is phenyl and Z ABe CH 3SO 3 -R-W-is 2-methoxyl group-3-aminomethyl phenyl, and Y is phenyl and Z ABe CH 3SO 3 -R-W-is 2,3-dihydrobenzo [b] furans-7-base, and Y is phenyl and Z ABe CH 3SO 3 -R-W-is naphthalene-2-base, and Y is phenyl and Z ABe CH 3SO 3 -R-W-is a 4-fluoro-3-trifluoromethyl, and Y is phenyl and Z ABe CH 3SO 3 -R-W-is 1,2,3, and 4-naphthane-5-base, Y are phenyl and Z ABe CH 3SO 3 -R-W-is 1,2,3, and 4-naphthane-6-base, Y are phenyl and Z ABe CH 3SO 3 -R-W-is a 5-chloro-2-p-methoxy-phenyl, and Y is phenyl and Z ABe CH 3SO 3 -R-W-is the 2-p-methoxy-phenyl, and Y is phenyl and Z ABe CH 3SO 3 -R-W-is the 2-trifluoromethyl, and Y is phenyl and Z ABe CH 3SO 3 -R-W-is the 2-isopropyl phenyl, and Y is phenyl and Z ABe CH 3SO 3 -R-W-is the 2-ethylphenyl, and Y is phenyl and Z ABe CH 3SO 3 -R-W-is the 2-Phenoxyphenyl, and Y is phenyl and Z ABe CH 3SO 3 -R-W-is a benzyl, and Y is phenyl and Z ABe CH 3SO 3 -R-W-is 3,5-two (trifluoromethyl) phenyl, and Y is phenyl and Z ABe Cl -R-W-is the 2-p-methoxy-phenyl, and Y is cyclohexyl and Z ABe CH 3SO 3 -R-W-is a 4-fluoro-3-trifluoromethyl, and Y is cyclohexyl and Z ABe CH 3SO 3 -R-W-is the 2-p-methoxy-phenyl, and Y is 3,5-3,5-dimethylphenyl and Z ABe CH 3SO 3 -Perhaps R-W-is the 2-p-methoxy-phenyl, and Y is naphthalene-2-base and Z ABe CH 3SO 3 -Perhaps Z in above-claimed cpd wherein AIt is another kind of pharmaceutically acceptable negatively charged ion.
21, the compound of claim 1; be 4-phenyl-1-(3 (S)-[3; the 4-dichlorophenyl]-4-[2-(1; 2,3,4-tetrahydrochysene-5-naphthoyl) imidazoles-1-yl] butyl) rubane mesylate or 4-phenyl-1-(3 (R)-[3; the 4-dichlorophenyl]-4-[2-(1; 2,3,4-tetrahydrochysene-5-naphthoyl) imidazoles-1-yl] butyl) the rubane mesylate.
22, R, R in a kind of method for preparing formula (I) compound of claim 1, formula (I) 1, W, X, Y, Ar and Z ASuch as claim 1 definition, this method comprises formula (II) compound
Figure A9880634200061
Wherein R, R 1, Ar, W and X such as preceding formula (I) compound is defined, Z can form pharmaceutically acceptable negatively charged ion (Z A) leavings group and Z 1Be leavings group, with the reaction of formula (III) compound,
Figure A9880634200062
Y such as preceding formula (I) compound is defined wherein is after the described method, (a) at Z 1During for leavings group, be exchanged for pharmaceutically acceptable negatively charged ion (Z A), perhaps (b) at random, at Z ADuring for pharmaceutically acceptable negatively charged ion, be exchanged for another kind of pharmaceutically acceptable negatively charged ion.
23, the method for claim 22, wherein Z is C 1-C 4Alkane sulfonyl oxy, phenylsulfonyloxy, tolysulfonyl oxygen base, chlorine, bromine or iodine, and Z 1It is trifluoro-methanesulfonyl oxy.
24, the method for claim 22, wherein Z is mesyloxy and Z AIt is methanesulfonate.
25, a kind of pharmaceutical composition contains each formula (I) compound and pharmaceutically acceptable diluent or the carrier just like claim 1-21.
26, claim 1-21 each formula (I) compound or its pharmaceutically acceptable composition of claim 25, be used as medicine respectively.
27, claim 1-21 each formula (I) compound or its pharmaceutically acceptable composition of claim 25 in preparation by the purposes in the medicine of the combination results antagonist action of a kind of tachykinin receptor or multiple tachykinin receptor being treated disease.
28, the purposes of claim 27, wherein antagonist action is at people NK 1And NK 2Tachykinin receptor.
29, claim 27 or 28 purposes, wherein disease is a diseases associated with inflammation, sacroiliitis for example, psoriasis, asthma or inflammatory bowel, central nervous system (CNS) disease, anxiety for example, depressed, dementia or psychosis, stomach-intestines (GI) disease, as the function enteropathy, irritable bowel syndrome, gastroesophageal reflux, scoracratia, colitis or regional ileitis, the disease that causes by the gram negative bacterium of helicobacter pylori or another kind of urease-positive, the urogenital tract disease, for example incontinence, hyperreflexia or urocystitis, tuberculosis, for example chronic disordered breathing tract disease, allergy, eczema for example, contact dermatitis, atopic dermatitis or rhinitis, anaphylactic disease, toxicodendron allergy for example, peripheral neurophaty, for example diabetic neuropathy, neurodynia, cusalgia, the painful neuropathy, burn, herpetic neurodynia or postherpetic neuralgia, vomiting, cough, migraine or acute and chronic pain.
30, a kind of by the combination results antagonist action of a kind of tachykinin receptor or multiple tachykinin receptor being treated the methods of treatment of human diseases, this method comprise with the claim 1-21 of significant quantity each formula (I) compound or the described mankind of its pharmaceutically acceptable combination treatment of claim 25.
31, the method for claim 30, antagonist action wherein are at people NK 1And NK 2Tachykinin receptor.
32, claim 30 or 31 method, wherein disease is a diseases associated with inflammation, sacroiliitis for example, psoriasis, asthma or inflammatory bowel, central nervous system (CNS) disease, anxiety for example, depressed, dementia or psychosis, stomach-intestines (GI) disease, as the function enteropathy, irritable bowel syndrome, gastroesophageal reflux, scoracratia, colitis or regional ileitis, the disease that causes by the gram negative bacterium of helicobacter pylori or another kind of urease-positive, the urogenital tract disease, for example incontinence, hyperreflexia or urocystitis, tuberculosis, for example chronic disordered breathing tract disease, allergy, eczema for example, contact dermatitis, atopic dermatitis or rhinitis, anaphylactic disease, toxicodendron allergy for example, peripheral neurophaty, for example diabetic neuropathy, neurodynia, cusalgia, the painful neuropathy, burn, herpetic neurodynia or postherpetic neuralgia, vomiting, cough, migraine or acute and chronic pain.
33, formula (II), (XI), (XII), (XIII), (XIV), (XV), (XXIII), (XXX) or (XXXI) compound:
Figure A9880634200081
Figure A9880634200091
Wherein R, R 1, W, X and Ar such as claim 1 definition, Z can form pharmaceutically acceptable negatively charged ion (Z A) leavings group, Z 1Be that leavings group and P are protecting groups.
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HUP0003962A3 (en) 2001-12-28
PT994876E (en) 2005-01-31
NO995782D0 (en) 1999-11-25
YU64699A (en) 2002-06-19
US6380396B1 (en) 2002-04-30
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ID23410A (en) 2000-04-20
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BR9810619A (en) 2000-09-12
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